Pyrido [4,3-b] indole and pyrido [3,4-b] indole derivatives and methods of use

ABSTRACT

This disclosure is directed to pyrido[4,3-b]indole and pyrido[3,4-b]indole derivatives. Pharmaceutical compositions comprising the compounds are also provided, as are methods of using the compounds in a variety of therapeutic applications, including the treatment of a cognitive disorder, psychotic disorder, neurotransmitter-mediated disorder and/or a neuronal disorder.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional Patent ApplicationNo. 61/305,900, filed Feb. 18, 2010, the disclosure of which is herebyincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Neurotransmitters such as histamine, serotonin, dopamine andnorepinephrine mediate a large number of processes in the centralnervous system (CNS) as well as outside the CNS. Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited to, Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia (such as cognitive impairment associated withschizophrenia (CIAS), positive symptoms, disorganized symptoms, andnegative symptoms of schizophrenia), anxiety, multiple sclerosis,stroke, traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression,attention-deficit disorder (ADD), attention-deficit hyperactivitydisorder (ADHD) and a variety of allergic diseases. Compounds thatmodulate these neurotransmitters may be useful therapeutics.

Histamine receptors belong to the superfamily of G protein-coupled seventransmembrane proteins. G protein-coupled receptors constitute one ofthe major signal transduction systems in eukaryotic cells. Codingsequences for these receptors, in those regions believed to contributeto the agonist-antagonist binding site, are strongly conserved acrossmammalian species. Histamine receptors are found in most peripheraltissue and within the central nervous system. Compounds capable ofmodulating a histamine receptor may find use in therapy, e.g., histamineantagonists may find use as antihistamines.

Dimebon is a known anti-histamine drug that has also been characterizedas a neuroprotective agent useful to treat, inter alia,neurodegenerative diseases. Dimebon has been shown to inhibit the deathof brain cells (neurons) in preclinical models of Alzheimer's diseaseand Huntington's disease, making it a novel potential treatment forthese and other neurodegenerative diseases. In addition, dimebon hasbeen shown to improve the mitochondrial function of cells in the settingof cellular stress with very high potency. For example, dimebontreatment improved mitochondrial function and increased the number ofsurviving cells after treatment with the cell toxin ionomycin in a dosedependent fashion. Dimebon has also been shown to promote neuriteoutgrowth and neurogenesis, processes important in the formation of newand/or enhanced neuronal cell connections, and evidence of dimebon'spotential for use in additional diseases or conditions. See, e.g., U.S.Pat. Nos. 6,187,785 and 7,071,206 and PCT Patent Application Nos.PCT/US2004/041081, PCT/US2007/020483, PCT/US2006/039077,PCT/US2008/077090, PCT/US2007/020516, PCT/US2007/022645,PCT/US2007/002117, PCT/US2008/006667, PCT/US2007/024626,PCT/US2008/009357, PCT/US2007/024623 and PCT/US2008/008121. Hydrogenatedpyrido[4,3-b]indoles and uses thereof have been disclosed in PCT PatentApplication Nos. PCT/US2008/081390, PCT/US2009/032065 andPCT/US2009/038142. Hydrogenated pyrido[3,4-b]indoles and uses thereofhave been described in PCT/US2009/038138. Azepino[4,5-b]indoles and usesthereof have been described in PCT/US2009/062872. All referencesdisclosed herein and throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although dimebon holds great promise as a drug for the treatment ofneurodegenerative diseases and/or diseases in which neurite outgrowthand/or neurogenesis may be implicated in therapy, there remains a needfor new and alternative therapies for the treatment of such diseases orconditions. In addition, there remains a need for new and alternativeantihistamine drugs, preferably ones in which side-effects such asdrowsiness are reduced or eliminated. Compounds that exhibit enhancedand/or more desirable properties than dimebon (e.g., superior safety andefficacy) may find particular use in the treatment of at least thoseindications for which dimebon is believed to be advantageous. Further,compounds that exhibit a different therapeutic profile than dimebon asdetermined, e.g., by in vitro and/or in vivo assays, may find use inadditional diseases and conditions.

BRIEF SUMMARY OF THE INVENTION

Hydrogenated pyrido[4,3-b]indoles and pyrido[3,4-b]indoles aredescribed. Compositions and kits comprising the compounds are alsoprovided, as are methods of using and making the compounds. Thecompounds provided herein may find use as new histamine receptormodulators, as well as modulators of other neurotransmitters. Compoundsprovided may also find use in treating neurodegenerative diseases.Compounds provided may also find use in treating diseases and/orconditions in which modulation of aminergic G protein-coupled receptorsand/or neurite outgrowth may be implicated in therapy. Compoundsdisclosed herein may find use in the methods disclosed herein, includinguse in treating, preventing, delaying the onset and/or delaying thedevelopment of a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder in anindividual in need thereof, such as humans.

In one aspect, compounds of the formula (IA) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R⁴are taken together to form an ethylene (—CH₂CH₂—) moiety or a propylene(—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In one variation, compounds of the formula (IA), and salts and solvatesthereof, are embraced, provided that at least one of X¹, X² and X³ is CHor CR⁶ and provisions (1)-(4) apply:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano,alkynyl, acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b)), oramino substituted with one or two substituted or unsubstituted C₁-C₈alkyl;

(2) when each m, n, o and p is 0 and R⁵ is methyl, then Q is substitutedor unsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula—CR⁹═CR^(10a)R^(10b), or amino substituted with one or two substitutedor unsubstituted C₁-C₈ alkyl;

(3) wherein at least one of m, n, o and p is 1 and R⁵ is H, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy,carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(4) wherein at least one of m, n, o and p is 1 and R⁵ is methyl, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl other than a substituted piperazinyl, aminoacyl, acyloxy,carboxyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a groupof the formula —CR⁹═CR^(10a)R^(10b), or amino substituted with one ortwo substituted or unsubstituted C₁-C₈ alkyl.

In some embodiments, the compound is of the formula (IA), where Q issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, compounds of the formula (IA) have the structures(C1)-(C5):

wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8c) is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^(8d) is H or substituted or unsubstituted C₁-C₈ alkyl, and the

bond indicates the presence of either an E or Z double bondconfiguration;

Y is O or NR¹¹;

each R¹¹, R^(12a) and R^(12b) is independently H or substituted orunsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl;

provided that when the compound is of the formula (C5), D is other thanunsubstituted phenyl.

In some embodiments, the compound is of the formula (C1). In someembodiments, wherein the compound is of the formula (C2). In someembodiments, the compound is of the formula (C3). In some embodiments,the compound is of the formula (C4). In some embodiments, the compoundis of the formula (C5).

In some embodiments, R¹ is H or methyl. In some embodiments, R⁵ is H ormethyl. In some embodiments, X¹ is CH. In some embodiments, X³ is CH. Insome embodiments, R⁶ is H, chloro or methyl. In some embodiments, R⁶ ismethyl. In some embodiments, R^(8c) is H, OH or methyl. In someembodiments, R^(8d) is H, or unsubstituted C₁-C₈ alkyl (e.g., methyl).In some embodiments, Y is NR¹¹. In some embodiments, R¹¹ is H or methyl.In some embodiments, each R^(12a) and R^(12b) is H. In some embodiments,D is selected from the group consisting of phenyl, 4-fluorophenyl,pyridin-4-yl, pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl,thiazol-2-yl, and 4-phenylthiazol-2-yl. In some embodiments, D isselected from the group consisting of 4-fluorophenyl, pyridin-4-yl,pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and4-phenylthiazol-2-yl.

In another aspect of the invention, compounds of the formula (IB) areprovided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(2a) and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(4a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R^(2a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In one variation, compounds of the formula (IB), and salts and solvatesthereof, are embraced, provided that at least one of X¹, X² and X³ is CHor CR⁶ and provisions (1)-(3) apply:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, cyano, alkynyl, aminocarbonylalkoxy,acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), or aminosubstituted with one or two substituted or unsubstituted C₁-C₈ alkyl;

(2) when each m, n, o and p is 0 and R⁵ is unsubstituted C₁-C₈ alkyl,then Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino,aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(3) when at least one of m, n, o and p is 1 and R⁵ is H, then Q issubstituted or unsubstituted aryl other than unsubstituted phenyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted amino, aminoacyl,acyloxy, cyano, alkynyl, aminocarbonylalkoxy, or is a group of theformula —CR⁹═CR^(10a)R^(10b).

In some embodiments, the compound is of the formula (IA), where Q issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In another aspect of the invention, compounds of the formula (J-1) to(J-5) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety ora cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h),where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol,—S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—SO₂-alkyl, —SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino,halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In another aspect of the invention, compounds of the formula (K-1) to(K-5) are provided:

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety ora cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In another aspect, the invention provides a method of treating acognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder or a neuronal disorder in an individual comprisingadministering to an individual in need thereof an effective amount of acompound of formulae (IA), (IB), (IA1), (IA2), (IA3), (A1), (A2), (A3),(A4), (A5), (IB), (B1), (B2), (B3), (B4), (B5), (B6), (B7), (B8), (B9),B(10), (C1), (C2), (C3), (C4), (C5), (J-1), (J-2), (J-3), (J-4), (J-5),(J-1a), (J-2a), (J-3a), (J-4-a), (J-5a), (J-1b), (J-1c), (J-1d), (K-1),(K-2), (K-3), (K-4), (K-5), (K-1a), (K-2a), (K-3a), (K-4-a) and (K-5a),or a salt or solvate thereof.

The invention also includes all salts of compounds referred to herein,such as pharmaceutically acceptable salts. The invention also includesN-oxides of the tertiary amines where one or more tertiary aminemoieties are present in the compounds described. The invention alsoincludes any or all of the stereochemical forms, including anyenantiomeric or diastereomeric forms and geometric isomers of thecompounds described, or mixtures thereof. Unless stereochemistry isexplicitly indicated in a chemical structure or name, the structure orname is intended to embrace all possible stereoisomers, includinggeometric isomers, of a compound depicted. Unless olefin geometry isexplicitly indicated, substituted olefinic bonds may be present as cisor trans or (Z) or (E) isomeric forms, or as mixtures thereof. Inaddition, where a specific stereochemical form is depicted, it isunderstood that other stereochemical forms are also embraced by theinvention. For example, where only a Z form of a compound isspecifically listed, it is understood that the E form of the compound isalso embraced. All forms of the compounds are also embraced by theinvention, such as crystalline or non-crystalline forms of thecompounds. Compositions comprising a compound of the invention are alsointended, such as a composition of substantially pure compound, which insome embodiments is a specific stereochemical form, including a specificgeometric isomer. Compositions comprising a mixture of compounds of theinvention in any ratio are also embraced by the invention, includingmixtures of two or more stereochemical forms of a compound of theinvention in any ratio, such that racemic, non-racemic, enantio-enrichedand scalemic mixtures of a compound are embraced, or mixtures thereof.

The invention is also directed to pharmaceutical compositions comprisinga compound of the invention and a pharmaceutically acceptable carrier orexcipient. Kits comprising a compound of the invention and instructionsfor use are also embraced by this invention. Compounds as detailedherein or a pharmaceutically acceptable salt thereof are also providedfor the manufacture of a medicament for the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

In one aspect, compounds of the invention are used to treat, prevent,delay the onset and/or delay the development of any one or more of thefollowing: cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders inindividuals in need thereof, such as humans. In one variation, compoundsof the invention are used to treat, prevent, delay the onset and/ordelay the development of diseases or conditions for which the modulationof an aminergic G protein-coupled receptor is believed to be or isbeneficial. In one variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of any oneor more of diseases or conditions for which neurite outgrowth and/orneurogenesis and/or neurotrophic effects are believed to be or arebeneficial. In another variation, compounds of the invention are used totreat, prevent, delay the onset and/or delay the development of diseasesor conditions for which the modulation of an aminergic G protein-coupledreceptor and neurite outgrowth and/or neurogenesis and/or neurotrophiceffects are believed to be or are beneficial. In one variation, thedisease or condition is a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder and/or a neuronal disorder.

In another aspect, compounds of the invention are used to improvecognitive function and/or reduce psychotic effects in an individual,comprising administering to an individual in need thereof an amount of acompound described herein or a pharmaceutically acceptable salt thereofeffective to improve cognitive function and/or reduce psychotic effects.

In a further aspect, compounds of the invention are used to stimulateneurite outgrowth and/or promote neurogenesis and/or enhanceneurotrophic effects in an individual comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to stimulate neuriteoutgrowth and/or to promote neurogenesis and/or to enhance neurotrophiceffects. Synapse loss is associated with a variety of neurodegenerativediseases and conditions including Alzheimer's disease, schizophrenia,Huntington's disease, Parkinson's disease, amyotrophic lateralsclerosis, stroke, head trauma and spinal cord injury. Compounds of theinvention that stimulate neurite outgrowth may have a benefit in thesesettings.

In another aspect, compounds described herein are used to modulate anaminergic G protein-coupled receptor comprising administering to anindividual in need thereof an amount of a compound described herein or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor. In one variation, a compound ofthe invention modulates at least one of the following receptors:adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)), serotoninreceptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇), dopaminereceptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂ and/or H₃).In another variation, at least two of the following receptors aremodulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/or α_(2B)),serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or 5-HT₇),dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g., H₁, H₂and/or H₃). In another variation, at least three of the followingreceptors are modulated: adrenergic receptor (e.g., α_(1D), α_(2A)and/or α_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆and/or 5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor(e.g., H₁, H₂ and/or H₃). In another variation, each of the followingreceptors is modulated: adrenergic receptor (e.g., α_(1D), α_(2A) and/orα_(2B)), serotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and/or5-HT₇), dopamine receptor (e.g., D_(2L)) and histamine receptor (e.g.,H₁, H₂ and/or H₃). In another variation, at least one of the followingreceptors is modulated: α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C),5-HT₇, D_(2L), H₁, H₂ and H₃. In another variation, at least one of thefollowing receptors is modulated: α_(1D), α_(2A), α_(2B), 5-HT_(2A),5-HT_(2C), 5-HT₆, 5-HT₇, D₂, H₁, H₂ and H₃. In another variation, atleast two or three or four or five or six or seven or eight or nine orten or eleven of the following receptors are modulated: α_(1D), α_(2A),α_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇, D_(2L), H₁, H₂ and H₃. Inanother variation, at least two or three or four or five or six or sevenor eight or nine or ten or eleven of the following receptors aremodulated: α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇,D₂, H₁, H₂ and H₃. In a particular variation, at least dopamine receptorD₂ is modulated. In still another variation, at least dopamine receptorD_(2L) is modulated. In another particular variation, at least dopaminereceptor D₂ and serotonin receptor 5-HT_(2A) are modulated. In anotherparticular variation, at least dopamine receptor D_(2L) and serotoninreceptor 5-HT_(2A) are modulated. In a further particular variation, atleast adrenergic receptors α_(1D), α_(2A), α_(2B) and serotonin receptor5-HT₆ are modulated. In another particular variation, at leastadrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆and one or more of serotonin receptor 5-HT₇, 5-HT_(2A), 5-HT_(2C) andhistamine receptor H₁ and H₂ are modulated. In a further particularvariation, histamine receptor H₁ is modulated. In another variation,compounds of the invention exhibit any receptor modulation activitydetailed herein and further stimulate neurite outgrowth and/orneurogenesis and/or enhance neurotrophic effects. In one variation,compounds detailed herein inhibit binding of a ligand to histaminereceptor H₁ and/or H₂ by less than about 80% as determined by a suitableassay known in the art such as the assays described herein. In anothervariation, binding of a ligand to histamine receptor H₁ and/or H₂ isinhibited by less than about any of 75%, 70%, 65%, 60%, 55%, or 50% asdetermined by a suitable assay known in the art such as the assaysdescribed herein. In a further variation, compounds detailed herein: (a)inhibit binding of a ligand to histamine receptor H₁ and/or H₂ by lessthan about 80% (which can in different variations be less than about anyof 75%, 70%, 65%, 60%, 55%, or 50%) as determined by a suitable assayknown in the art such as the assays described herein and (b) inhibitbinding of a ligand to dopamine receptor D_(2L) by greater than aboutany of 80%, 85%, 90%, 95%, 100% or between about 85% and about 95% orbetween about 90% and about 100%, as determined in a suitable assayknown in the art such as the assays described herein. In a furthervariation, compounds detailed herein: (a) inhibit binding of a ligand tohistamine receptor H₁ and/or H₂ by less than about 80% (which can indifferent variations be less than about any of 75%, 70%, 65%, 60%, 55%,or 50%) as determined by a suitable assay known in the art such as theassays described herein and (b) inhibit binding of a ligand to adopamine receptor D₂ by greater than about any of 80%, 85%, 90%, 95%,100% or between about 85% and about 95% or between about 90% and about100%, as determined in a suitable assay known in the art such as theassays described herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

For use herein, unless clearly indicated otherwise, use of the terms“a”, “an” and the like refers to one or more.

As used herein, reference to “about” a value or parameter hereinincludes (and describes) embodiments that are directed to that value orparameter per se. For example, description referring to “about X”includes description of “X”.

As used herein, the term “aminergic G protein-coupled receptors” refersto a family of transmembrane proteins involved in cellularcommunication. Aminergic G protein coupled receptors are activated bybiogenic amines and represent a subclass of the superfamily of G proteincoupled receptors, which are structurally characterized by seventransmembrane helices. Aminergic G protein-coupled receptors include butare not limited to adrenergic receptors, serotonin receptors, dopaminereceptors, histamine receptors and imidazoline receptors.

As used herein, the term “adrenergic receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toan adrenergic receptor or reduces or eliminates or increases or enhancesor mimics an activity of an adrenergic receptor. As such, an “adrenergicreceptor modulator” encompasses both an adrenergic receptor antagonistand an adrenergic receptor agonist. In some aspects, the adrenergicreceptor modulator binds to or inhibits binding to a ligand to anα1-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) and/orreduces or eliminates or increases or enhances or mimics an activity ofa α₁-adrenergic receptor (e.g., α_(1A), α_(1B) and/or α_(1D)) and/or aα₂-adrenergic receptor (e.g., α_(2A), α_(2B) and/or α_(2C)) in areversible or irreversible manner. In some aspects, the adrenergicreceptor modulator inhibits binding of a ligand by at least about orabout any one of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or100% as determined in the assays described herein. In some aspects, theadrenergic receptor modulator reduces an activity of an adrenergicreceptor by at least or about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%,80%, 90%, 95% or 100% as compared to the corresponding activity in thesame subject prior to treatment with the adrenergic receptor modulatoror compared to the corresponding activity in other subjects notreceiving the adrenergic receptor modulator. In some aspects, theadrenergic receptor modulator enhances an activity of an adrenergicreceptor by at least about or about any of 10%, 20%, 30%, 40%, 50%, 60%,70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% or more ascompared to the corresponding activity in the same subject prior totreatment with the adrenergic receptor modulator or compared to thecorresponding activity in other subjects not receiving the adrenergicreceptor modulator. In some aspects, the adrenergic receptor modulatoris capable of binding to the active site of an adrenergic receptor(e.g., a binding site for a ligand). In some embodiments, the adrenergicreceptor modulator is capable of binding to an allosteric site of anadrenergic receptor.

As used herein, the term “dopamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa dopamine receptor or reduces or eliminates or increases or enhances ormimics an activity of a dopamine receptor. As such, a “dopamine receptormodulator” encompasses both a dopamine receptor antagonist and adopamine receptor agonist. In some aspects, the dopamine receptormodulator binds to or inhibits binding of a ligand to a dopamine-1 (D₁)and/or a dopamine-2 (D₂) receptor or reduces or eliminates or increasesor enhances or mimics an activity of a dopamine-1 (D₁) and/or adopamine-2 (D₂) receptor in a reversible or irreversible manner.Dopamine D₂ receptors are divided into two categories, D_(2L) andD_(2S), which are formed from a single gene by differential splicing.D_(2L) receptors have a longer intracellular domain than D_(2S). In someembodiments, the dopamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the dopamine receptor modulator reduces anactivity of a dopamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thedopamine receptor modulator or compared to the corresponding activity inother subjects not receiving the dopamine receptor modulator. In someembodiments, the dopamine receptor modulator enhances an activity of adopamine receptor by at least about or about any of 10%, 20%, 30%, 40%,50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500% ormore as compared to the corresponding activity in the same subject priorto treatment with the dopamine receptor modulator or compared to thecorresponding activity in other subjects not receiving the dopaminereceptor modulator. In some embodiments, the dopamine receptor modulatoris capable of binding to the active site of a dopamine receptor (e.g., abinding site for a ligand). In some embodiments, the dopamine receptormodulator is capable of binding to an allosteric site of a dopaminereceptor.

As used herein, the term “serotonin receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa serotonin receptor or reduces or eliminates or increases or enhancesor mimics an activity of a serotonin receptor. As such, a “serotoninreceptor modulator” encompasses both a serotonin receptor antagonist anda serotonin receptor agonist. In some embodiments, the serotoninreceptor modulator binds to or inhibits binding of a ligand to a5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A) and/or a 5-HT_(2B)and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄ and/or a 5-HT₆ and/or a5-HT₇ receptor or reduces or eliminates or increases or enhances ormimics an activity of a 5-HT_(1A) and/or a 5-HT_(1B) and/or a 5-HT_(2A)and/or a 5-HT_(2B) and/or a 5-HT_(2C) and/or a 5-HT₃ and/or a 5-HT₄and/or a 5-HT₆ and/or a 5-HT₇ receptor in a reversible or irreversiblemanner. In some embodiments, the serotonin receptor modulator inhibitsbinding of a ligand by at least about or about any one of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as determined in the assaysdescribed herein. In some embodiments, the serotonin receptor modulatorreduces an activity of a serotonin receptor by at least about or aboutany of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% ascompared to the corresponding activity in the same subject prior totreatment with the serotonin receptor modulator or compared to thecorresponding activity in other subjects not receiving the serotoninreceptor modulator. In some embodiments, the serotonin receptormodulator enhances an activity of a serotonin receptor by at least aboutor about any of 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100or 200% or 300% or 400% or 500% or more as compared to the correspondingactivity in the same subject prior to treatment with the serotoninreceptor modulator or compared to the corresponding activity in othersubjects not receiving the serotonin receptor modulator. In someembodiments, the serotonin receptor modulator is capable of binding tothe active site of a serotonin receptor (e.g., a binding site for aligand). In some embodiments, the serotonin receptor modulator iscapable of binding to an allosteric site of a serotonin receptor.

As used herein, the term “histamine receptor modulator” intends andencompasses a compound that binds to or inhibits binding of a ligand toa histamine receptor or reduces or eliminates or increases or enhancesor mimics an activity of a histamine receptor. As such, a “histaminereceptor modulator” encompasses both a histamine receptor antagonist anda histamine receptor agonist. In some embodiments, the histaminereceptor modulator binds to or inhibits binding of a ligand to ahistamine H₁ and/or H₂ and/or H₃ receptor or reduces or eliminates orincreases or enhances or mimics an activity of a histamine H₁ and/or H₂and/or H₃ receptor in a reversible or irreversible manner. In someembodiments, the histamine receptor modulator inhibits binding of aligand by at least about or about any one of 10%, 20%, 30%, 40%, 50%,60%, 70%, 80%, 90%, 95% or 100% as determined in the assays describedherein. In some embodiments, the histamine receptor modulator reduces anactivity of a histamine receptor by at least about or about any of 10%,20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95% or 100% as compared to thecorresponding activity in the same subject prior to treatment with thehistamine receptor modulator or compared to the corresponding activityin other subjects not receiving the histamine receptor modulator. Insome embodiments, the histamine receptor modulator enhances an activityof a histamine receptor by at least about or about any of 10%, 20%, 30%,40%, 50%, 60%, 70%, 80%, 90%, 95% or 100 or 200% or 300% or 400% or 500%or more as compared to the corresponding activity in the same subjectprior to treatment with the histamine receptor modulator or compared tothe corresponding activity in other subjects not receiving the histaminereceptor modulator. In some embodiments, the histamine receptormodulator is capable of binding to the active site of a histaminereceptor (e.g., a binding site for a ligand). In some embodiments, thehistamine receptor modulator is capable of binding to an allosteric siteof a histamine receptor.

Unless clearly indicated otherwise, “an individual” as used hereinintends a mammal, including but not limited to a human, bovine, primate,equine, canine, feline, porcine, and ovine animals. Thus, the inventionfinds use in both human medicine and in the veterinary context,including use in agricultural animals and domestic pets. The individualmay be a human who has been diagnosed with or is suspected of having acognitive disorder, a psychotic disorder, a neurotransmitter-mediateddisorder and/or a neuronal disorder. The individual may be a human whoexhibits one or more symptoms associated with a cognitive disorder, apsychotic disorder, a neurotransmitter-mediated disorder and/or aneuronal disorder. The individual may be a human who has a mutated orabnormal gene associated with a cognitive disorder, a psychoticdisorder, a neurotransmitter-mediated disorder and/or a neuronaldisorder. The individual may be a human who is genetically or otherwisepredisposed to developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder.

As used herein, “treatment” or “treating” is an approach for obtaining abeneficial or desired result, such as a clinical result. For purposes ofthis invention, beneficial or desired clinical results include, but arenot limited to, alleviation of a symptom and/or diminishment of theextent of a symptom and/or preventing a worsening of a symptomassociated with a disease or condition. In one variation, beneficial ordesired clinical results include, but are not limited to, alleviation ofa symptom and/or diminishment of the extent of a symptom and/orpreventing a worsening of a symptom associated with a cognitivedisorder, a psychotic disorder, a neurotransmitter-mediated disorderand/or a neuronal disorder. Preferably, treatment of a disease orcondition with a compound of the invention or a pharmaceuticallyacceptable salt thereof is accompanied by no or fewer side effects thanare associated with currently available therapies for the disease orcondition and/or improves the quality of life of the individual.

As used herein, “delaying” development of a disease or condition meansto defer, hinder, slow, retard, stabilize and/or postpone development ofthe disease or condition. This delay can be of varying lengths of time,depending on the history of the disease and/or individual being treated.As is evident to one skilled in the art, a sufficient or significantdelay can, in effect, encompass prevention, in that the individual doesnot develop the disease or condition. For example, a method that“delays” development of Alzheimer's disease is a method that reducesprobability of disease development in a given time frame and/or reducesextent of the disease in a given time frame, when compared to not usingthe method. Such comparisons are typically based on clinical studies,using a statistically significant number of subjects. For example,Alzheimer's disease development can be detected using standard clinicaltechniques, such as routine neurological examination, patient interview,neuroimaging, detecting alterations of levels of specific proteins inthe serum or cerebrospinal fluid (e.g., amyloid peptides and Tau),computerized tomography (CT) or magnetic resonance imaging (MRI).Similar techniques are known in the art for other diseases andconditions. Development may also refer to disease progression that maybe initially undetectable and includes occurrence, recurrence and onset.

As used herein, an “at risk” individual is an individual who is at riskof developing a cognitive disorder, a psychotic disorder, aneurotransmitter-mediated disorder and/or a neuronal disorder that canbe treated with a compound of the invention. An individual “at risk” mayor may not have a detectable disease or condition, and may or may nothave displayed detectable disease prior to the treatment methodsdescribed herein. “At risk” denotes that an individual has one or moreso-called risk factors, which are measurable parameters that correlatewith development of a disease or condition and are known in the art. Anindividual having one or more of these risk factors has a higherprobability of developing the disease or condition than an individualwithout these risk factor(s). These risk factors include, but are notlimited to, age, sex, race, diet, history of previous disease, presenceof precursor disease, genetic (i.e., hereditary) considerations, andenvironmental exposure. For example, individuals at risk for Alzheimer'sdisease include, e.g., those having relatives who have experienced thisdisease and those whose risk is determined by analysis of genetic orbiochemical markers. Genetic markers of risk for Alzheimer's diseaseinclude mutations in the APP gene, particularly mutations at position717 and positions 670 and 671 referred to as the Hardy and Swedishmutations, respectively (Hardy, Trends Neurosci., 20:154-9, 1997). Othermarkers of risk are mutations in the presenilin genes (e.g., PS1 orPS2), ApoE4 alleles, a family history of Alzheimer's disease,hypercholesterolemia and/or atherosclerosis. Other such factors areknown in the art for other diseases and conditions.

As used herein, the term “pro-cognitive” includes but is not limited toan improvement of one or more mental processes such as memory,attention, perception and/or thinking, which may be assessed by methodsknown in the art.

As used herein, the term “neurotrophic” effects includes but is notlimited to effects that enhance neuron function such as growth, survivaland/or neurotransmitter synthesis.

As used herein, the term “cognitive disorders” refers to and intendsdiseases and conditions that are believed to involve or be associatedwith or do involve or are associated with progressive loss of structureand/or function of neurons, including death of neurons, and where acentral feature of the disorder may be the impairment of cognition(e.g., memory, attention, perception and/or thinking). These disordersinclude pathogen-induced cognitive dysfunction, e.g. HIV associatedcognitive dysfunction and Lyme disease associated cognitive dysfunction.Examples of cognitive disorders include Alzheimer's Disease,Huntington's Disease, Parkinson's Disease, schizophrenia, amyotrophiclateral sclerosis (ALS), autism, mild cognitive impairment (MCI),stroke, traumatic brain injury (TBI) and age-associated memoryimpairment (AAMI).

As used herein, the term “psychotic disorders” refers to and intendsmental diseases or conditions that are believed to cause or do causeabnormal thinking and perceptions. Psychotic disorders are characterizedby a loss of reality which may be accompanied by delusions,hallucinations (perceptions in a conscious and awake state in theabsence of external stimuli which have qualities of real perception, inthat they are vivid, substantial, and located in external objectivespace), personality changes and/or disorganized thinking. Other commonsymptoms include unusual or bizarre behavior, as well as difficulty withsocial interaction and impairment in carrying out the activities ofdaily living. Exemplary psychotic disorders are schizophrenia, bipolardisorders, psychosis, anxiety and depression.

As used herein, the term “neurotransmitter-mediated disorders” refers toand intends diseases or conditions that are believed to involve or beassociated with or do involve or are associated with abnormal levels ofneurotransmitters such as histamine, serotonin, dopamine, norepinephrineor impaired function of aminergic G protein-coupled receptors. Exemplaryneurotransmitter-mediated disorders include spinal cord injury, diabeticneuropathy, allergic diseases and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Abnormalneurotransmitter levels are associated with a wide variety of diseasesand conditions including, but not limited, to Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, schizophrenia, anxiety, multiple sclerosis, stroke,traumatic brain injury, spinal cord injury, diabetic neuropathy,fibromyalgia, bipolar disorders, psychosis, depression and a variety ofallergic diseases.

As used herein, the term “neuronal disorders” refers to and intendsdiseases or conditions that are believed to involve, or be associatedwith, or do involve or are associated with neuronal cell death and/orimpaired neuronal function or decreased neuronal function. Exemplaryneuronal indications include neurodegenerative diseases and disorderssuch as Alzheimer's disease, Huntington's disease, amyotrophic lateralsclerosis (ALS), Parkinson's disease, canine cognitive dysfunctionsyndrome (CCDS), Lewy body disease, Menkes disease, Wilson disease,Creutzfeldt-Jakob disease, Fahr disease, an acute or chronic disorderinvolving cerebral circulation, such as ischemic or hemorrhagic strokeor other cerebral hemorrhagic insult, age-associated memory impairment(AAMI), mild cognitive impairment (MCI), injury-related mild cognitiveimpairment (MCI), post-concussion syndrome, post-traumatic stressdisorder, adjuvant chemotherapy, traumatic brain injury (TBI), neuronaldeath mediated ocular disorder, macular degeneration, age-relatedmacular degeneration, autism, including autism spectrum disorder,Asperger syndrome, and Rett syndrome, an avulsion injury, a spinal cordinjury, myasthenia gravis, Guillain-Barré syndrome, multiple sclerosis,diabetic neuropathy, fibromyalgia, neuropathy associated with spinalcord injury, schizophrenia, bipolar disorder, psychosis, anxiety ordepression.

As used herein, the term “neuron” represents a cell of ectodermalembryonic origin derived from any part of the nervous system of ananimal. Neurons express well-characterized neuron-specific markers,including neurofilament proteins, NeuN (Neuronal Nuclei marker), MAP2,and class III tubulin. Included as neurons are, for example,hippocampal, cortical, midbrain dopaminergic, spinal motor, sensory,sympathetic, septal cholinergic, and cerebellar neurons.

As used herein, the term “neurite outgrowth” or “neurite activation”refers to the extension of existing neuronal processes (e.g., axons anddendrites) and the growth or sprouting of new neuronal processes (e.g.,axons and dendrites). Neurite outgrowth or neurite activation may alterneural connectivity, resulting in the establishment of new synapses orthe remodeling of existing synapses.

As used herein, the term “neurogenesis” refers to the generation of newnerve cells from undifferentiated neuronal progenitor cells, also knownas multipotential neuronal stem cells. Neurogenesis actively producesnew neurons, astrocytes, glia, Schwann cells, oligodendrocytes and/orother neural lineages. Much neurogenesis occurs early in humandevelopment, though it continues later in life, particularly in certainlocalized regions of the adult brain.

As used herein, the term “neural connectivity” refers to the number,type, and quality of connections (“synapses”) between neurons in anorganism. Synapses form between neurons, between neurons and muscles (a“neuromuscular junction”), and between neurons and other biologicalstructures, including internal organs, endocrine glands, and the like.Synapses are specialized structures by which neurons transmit chemicalor electrical signals to each other and to non-neuronal cells, muscles,tissues, and organs. Compounds that affect neural connectivity may do soby establishing new synapses (e.g., by neurite outgrowth or neuriteactivation) or by altering or remodeling existing synapses. Synapticremodeling refers to changes in the quality, intensity or type of signaltransmitted at particular synapses.

As used herein, the term “neuropathy” refers to a disorder characterizedby altered function and/or structure of motor, sensory, and autonomicneurons of the nervous system, initiated or caused by a primary lesionor other dysfunction of the nervous system. Patterns of peripheralneuropathy include polyneuropathy, mononeuropathy, mononeuritismultiplex and autonomic neuropathy. The most common form is(symmetrical) peripheral polyneuropathy, which mainly affects the feetand legs. A radiculopathy involves spinal nerve roots, but if peripheralnerves are also involved the term radiculoneuropathy is used. The formof neuropathy may be further broken down by cause, or the size ofpredominant fiber involvement, e.g., large fiber or small fiberperipheral neuropathy. Central neuropathic pain can occur in spinal cordinjury, multiple sclerosis, and some strokes, as well as fibromyalgia.Neuropathy may be associated with varying combinations of weakness,autonomic changes and sensory changes. Loss of muscle bulk orfasciculations, a particular fine twitching of muscle may also be seen.Sensory symptoms encompass loss of sensation and “positive” phenomenaincluding pain. Neuropathies are associated with a variety of disorders,including diabetes (e.g., diabetic neuropathy), fibromyalgia, multiplesclerosis, and herpes zoster infection, as well as with spinal cordinjury and other types of nerve damage.

As used herein, the term “Alzheimer's disease” refers to a degenerativebrain disorder characterized clinically by progressive memory deficits,confusion, behavioral problems, inability to care for oneself, gradualphysical deterioration and, ultimately, death. Histologically, thedisease is characterized by neuritic plaques, found primarily in theassociation cortex, limbic system and basal ganglia. The majorconstituent of these plaques is amyloid beta peptide (Aβ), which is thecleavage product of beta amyloid precursor protein (βAPP or APP). APP isa type I transmembrane glycoprotein that contains a large ectopicN-terminal domain, a transmembrane domain and a small cytoplasmicC-terminal tail. Alternative splicing of the transcript of the singleAPP gene on chromosome 21 results in several isoforms that differ in thenumber of amino acids. Aβ appears to have a central role in theneuropathology of Alzheimer's disease. Familial forms of the diseasehave been linked to mutations in APP and the presenilin genes (Tanzi etal, Neurobiol. Dis. 3:159-168, 1996; Hardy, Ann. Med. 28:255-258, 1996).Diseased-linked mutations in these genes result in increased productionof the 42-amino acid form of Aβ, the predominant form found in amyloidplaques. Mitochondrial dysfunction has also been reported to be animportant component of Alzheimer's disease (Bubber et al, Mitochondrialabnormalities in Alzheimer brain: Mechanistic Implications, Ann. Neurol.57(5):695-703, 2005; Wang et al, Insights into amyloid-β-inducedmitochondrial dysfunction in Alzheimer disease, Free Radical Biology &Medicine 43:1569-1573, 2007; Swerdlow et al, Mitochondria in Alzheimer'sdisease, Int. Rev. Neurobiol. 53:341-385, 2002; and Reddy et al, Aremitochondria critical in the pathogenesis of Alzheimer's disease?, BrainRes Rev. 49(3):618-32, 2005). It has been proposed that mitochondrialdysfunction has a causal relationship with neuronal function (includingneurotransmitter synthesis and secretion) and viability. Compounds whichstabilize mitochondria may therefore have a beneficial impact onAlzheimer's patients.

As used herein, the term “Huntington's disease” refers to a fatalneurological disorder characterized clinically by symptoms such asinvoluntary movements, cognition impairment or loss of cognitivefunction and a wide spectrum of behavioral disorders. Common motorsymptoms associated with Huntington's disease include chorea(involuntary writhing and spasming), clumsiness, and progressive loss ofthe abilities to walk, speak (e.g., exhibiting slurred speech) andswallow. Other symptoms of Huntington's disease can include cognitivesymptoms such as loss of intellectual speed, attention and short-termmemory and/or behavioral symptoms that can span the range of changes inpersonality, depression, irritability, emotional outbursts and apathy.Clinical symptoms typically appear in the fourth or fifth decade oflife. Huntington's disease is a devastating and often protractedillness, with death usually occurring approximately 10-20 years afterthe onset of symptoms. Huntington's disease is inherited through amutated or abnormal gene encoding an abnormal protein called the mutanthuntingtin protein; the mutated huntingtin protein produces neuronaldegeneration in many different regions of the brain. The degenerationfocuses on neurons located in the basal ganglia, structures deep withinthe brain that control many important functions including coordinatingmovement, and on neurons on the outer surface of the brain or cortex,which controls thought, perception and memory.

“Amyotrophic lateral sclerosis” or “ALS” is used herein to denote aprogressive neurodegenerative disease that affects upper motor neurons(motor neurons in the brain) and/or lower motor neurons (motor neuronsin the spinal cord) and results in motor neuron death. As used herein,the term “ALS” includes all of the classifications of ALS known in theart, including, but not limited to classical ALS (typically affectingboth lower and upper motor neurons), Primary Lateral Sclerosis (PLS,typically affecting only the upper motor neurons), Progressive BulbarPalsy (PBP or Bulbar Onset, a version of ALS that typically begins withdifficulties swallowing, chewing and speaking), Progressive MuscularAtrophy (PMA, typically affecting only the lower motor neurons) andfamilial ALS (a genetic version of ALS).

The term “Parkinson's disease” as used herein refers to any medicalcondition wherein an individual experiences one or more symptomsassociated with Parkinson's disease, such as without limitation one ormore of the following symptoms: rest tremor, cogwheel rigidity,bradykinesia, postural reflex impairment, symptoms having good responseto 1-dopa treatment, the absence of prominent oculomotor palsy,cerebellar or pyramidal signs, amyotrophy, dyspraxia and/or dysphasia.In a specific embodiment, the present invention is utilized for thetreatment of a dopaminergic dysfunction-related disorder. In a specificembodiment, the individual with Parkinson's disease has a mutation orpolymorphism in a synuclein, parkin or NURR1 nucleic acid that isassociated with Parkinson's disease. In one embodiment, the individualwith Parkinson's disease has defective or decreased expression of anucleic acid or a mutation in a nucleic acid that regulates thedevelopment and/or survival of dopaminergic neurons.

As used herein, the term “canine cognitive dysfunction syndrome,” or“CCDS” refers to an age-related deterioration of mental functiontypified by multiple cognitive impairments that affect an afflictedcanine's ability to function normally. The decline in cognitive abilitythat is associated with CCDS cannot be completely attributed to ageneral medical condition such as neoplasia, infection, sensoryimpairment, or organ failure. Diagnosis of CCDS in canines, such asdogs, is generally a diagnosis of exclusion, based on thorough behaviorand medical histories and the presence of clinical symptoms of CCDS thatare unrelated to other disease processes. Owner observation ofage-related changes in behavior is a practical means used to detect thepossible onset of CCDS in aging domestic dogs. A number of laboratorycognitive tasks may be used to help diagnose CCDS, while blood counts,chemistry panels and urinalysis can be used to rule out other underlyingdiseases that could mimic the clinical symptoms of CCDS. Symptoms ofCCDS include memory loss, which in domestic dogs may be manifested bydisorientation and/or confusion, decreased or altered interaction withfamily members and/or greeting behavior, changes in sleep-wake cycle,decreased activity level, and loss of house training or frequent,inappropriate elimination. A canine suffering from CCDS may exhibit oneor more of the following clinical or behavioral symptoms: decreasedappetite, decreased awareness of surroundings, decreased ability torecognize familiar places, people or other animals, decreased hearing,decreased ability to climb up and down stairs, decreased tolerance tobeing alone, development of compulsive behavior or repetitive behaviorsor habits, circling, tremors or shaking, disorientation, decreasedactivity level, abnormal sleep wake cycles, loss of house training,decreased or altered responsiveness to family members, and decreased oraltered greeting behavior. CCDS can dramatically affect the health andwell-being of an afflicted canine. Moreover, the companionship offeredby a pet with CCDS can become less rewarding as the severity of thedisease increases and its symptoms become more severe.

As used herein, the term “age-associated memory impairment” or “AAMI”refers to a condition that may be identified as GDS stage 2 on theglobal deterioration scale (GDS) (Reisberg et al, Am. J. Psychiatry139:1136-1139, 1982) which differentiates the aging process andprogressive degenerative dementia in seven major stages. The first stageof the GDS is one in which individuals at any age have neithersubjective complaints of cognitive impairment nor objective evidence ofimpairment. These GDS stage 1 individuals are considered normal. Thesecond stage of the GDS applies to those generally elderly persons whocomplain of memory and cognitive functioning difficulties such as notrecalling names as well as they could five or ten years previously ornot recalling where they have placed things as well as they could fiveor ten years previously. These subjective complaints appear to be verycommon in otherwise normal elderly individuals. AAMI refers to personsin GDS stage 2, who may differ neurophysiologically from elderly personswho are normal and free of subjective complaints, i.e., GDS stage 1. Forexample, AAMI subjects have been found to have more electrophysiologicslowing on a computer analyzed EEG than GDS stage 1 elderly persons(Prichep et al, Neurobiol. Aging 15:85-90, 1994).

As used herein, the term “mild cognitive impairment” or “MCI” refers toa type of cognitive disorder characterized by a more pronounceddeterioration in cognitive functions than is typical for normalage-related decline. As a result, elderly or aged patients with MCI havegreater than normal difficulty performing complex daily tasks andlearning, but without the inability to perform normal social, everyday,and/or professional functions typical of patients with Alzheimer'sdisease, or other similar neurodegenerative disorders eventuallyresulting in dementia. MCI is characterized by subtle, clinicallymanifest deficits in cognition, memory, and functioning, amongst otherimpairments, which are not of sufficient magnitude to fulfill criteriafor diagnosis of Alzheimer's disease or other dementia. MCI alsoencompasses injury-related MCI, defined herein as cognitive impairmentresulting from certain types of injury, such as nerve injury (e.g.,battlefield injuries, including post-concussion syndrome, and the like),neurotoxic treatment (e.g., adjuvant chemotherapy resulting in “chemobrain” and the like), and tissue damage resulting from physical injuryor other neurodegeneration, which is separate and distinct from mildcognitive impairment resulting from stroke, ischemia, hemorrhagicinsult, blunt force trauma, and the like.

As used herein, the term “traumatic brain injury” or “TBI” refers to abrain injury caused by a sudden trauma, such as a blow or jolt or apenetrating head injury, which disrupts the function or damages thebrain. Symptoms of TBI can range from mild, moderate to severe and cansignificantly affect many cognitive (deficits of language andcommunication, information processing, memory, and perceptual skills),physical (ambulation, balance, coordination, fine motor skills,strength, and endurance), and psychological skills.

“Neuronal death mediated ocular disease” intends an ocular disease inwhich death of the neuron is implicated in whole or in part. The diseasemay involve death of photoreceptors. The disease may involve retinalcell death. The disease may involve ocular nerve death by apoptosis.Particular neuronal death mediated ocular diseases include but are notlimited to macular degeneration, glaucoma, retinitis pigmentosa,congenital stationary night blindness (Oguchi disease), childhood onsetsevere retinal dystrophy, Leber congenital amaurosis, Bardet-Biedlesyndrome, Usher syndrome, blindness from an optic neuropathy, Leber'shereditary optic neuropathy, color blindness and Hansen-Larson-Bergsyndrome.

As used herein, the term “macular degeneration” includes all forms andclassifications of macular degeneration known in the art, including, butnot limited to diseases that are characterized by a progressive loss ofcentral vision associated with abnormalities of Bruch's membrane, thechoroid, the neural retina and/or the retinal pigment epithelium. Theterm thus encompasses disorders such as age-related macular degeneration(ARMD) as well as rarer, earlier-onset dystrophies that in some casescan be detected in the first decade of life. Other maculopathies includeNorth Carolina macular dystrophy, Sorsby's fundus dystrophy, Stargardt'sdisease, pattern dystrophy, Best disease, and Malattia Leventinese.

As used herein, the term “autism” refers to a brain development disorderthat impairs social interaction and communication and causes restrictedand repetitive behavior, typically appearing during infancy or earlychildhood. The cognitive and behavioral defects are thought to result inpart from altered neural connectivity. Autism encompasses relateddisorders sometimes referred to as “autism spectrum disorder,” as wellas Asperger syndrome and Rett syndrome.

As used herein, the term “nerve injury” or “nerve damage” refers tophysical damage to nerves, such as avulsion injury (e.g., where a nerveor nerves have been torn or ripped) or spinal cord injury (e.g., damageto white matter or myelinated fiber tracts that carry sensation andmotor signals to and from the brain). Spinal cord injury can occur frommany causes, including physical trauma (e.g., car accidents, sportsinjuries, and the like), tumors impinging on the spinal column,developmental disorders, such as spina bifida, and the like.

As used herein, the term “myasthenia gravis” or “MG” refers to anon-cognitive neuromuscular disorder caused by immune-mediated loss ofacetylcholine receptors at neuromuscular junctions of skeletal muscle.Clinically, MG typically appears first as occasional muscle weakness inapproximately two-thirds of patients, most commonly in the extraocularmuscles. These initial symptoms eventually worsen, producing droopingeyelids (ptosis) and/or double vision (diplopia), often causing thepatient to seek medical attention. Eventually, many patients developgeneral muscular weakness that may fluctuate weekly, daily, or even morefrequently. Generalized MG often affects muscles that control facialexpression, chewing, talking, swallowing, and breathing; before recentadvances in treatment, respiratory failure was the most common cause ofdeath.

As used herein, the term “Guillain-Barré syndrome” refers to anon-cognitive disorder in which the body's immune system attacks part ofthe peripheral nervous system. The first symptoms of this disorderinclude varying degrees of weakness or tingling sensations in the legs.In many instances the weakness and abnormal sensations spread to thearms and upper body. These symptoms can increase in intensity untilcertain muscles cannot be used at all and, when severe, the patient isalmost totally paralyzed. In these cases the disorder is lifethreatening—potentially interfering with breathing and, at times, withblood pressure or heart rate—and is considered a medical emergency. Mostpatients, however, recover from even the most severe cases ofGuillain-Barré syndrome, although some continue to have a certain degreeof weakness.

As used herein, the term “multiple sclerosis” or “MS” refers to anautoimmune condition in which the immune system attacks the centralnervous system (CNS), leading to demyelination of neurons. It may causenumerous symptoms, many of which are non-cognitive, and often progressesto physical disability. MS affects the areas of the brain and spinalcord known as the white matter. White matter cells carry signals betweenthe grey matter areas, where the processing is done, and the rest of thebody. More specifically, MS destroys oligodendrocytes which are thecells responsible for creating and maintaining a fatty layer, known asthe myelin sheath, which helps the neurons carry electrical signals. MSresults in a thinning or complete loss of myelin and, less frequently,the cutting (transection) of the neuron's extensions or axons. When themyelin is lost, the neurons can no longer effectively conduct theirelectrical signals. Almost any neurological symptom can accompany thedisease. MS takes several forms, with new symptoms occurring either indiscrete attacks (relapsing forms) or slowly accumulating over time(progressive forms). Most people are first diagnosed withrelapsing-remitting MS but develop secondary-progressive MS (SPMS) aftera number of years. Between attacks, symptoms may go away completely, butpermanent neurological problems often persist, especially as the diseaseadvances.

As used herein, the term “schizophrenia” refers to a chronic, mentaldisorder characterized by one or more positive symptoms (e.g., delusionsand hallucinations) and/or negative symptoms (e.g., blunted emotions andlack of interest) and/or disorganized symptoms (e.g., disorganizedthinking and speech or disorganized perception and behavior).Schizophrenia as used herein includes all forms and classifications ofschizophrenia known in the art, including, but not limited to catatonictype, hebephrenic type, disorganized type, paranoid type, residual typeor undifferentiated type schizophrenia and deficit syndrome and/or thosedescribed in American Psychiatric Association: Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition, Washington D.C.,2000 or in International Statistical Classification of Diseases andRelated Health Problems, or otherwise known to those of skill in theart.

“Cognitive impairment associated with schizophrenia” or “CIAS” includesneuropsychological deficits in attention, working memory, verballearning, and problem solving. These deficits are believed to be linkedto impairment in functional status (e.g., social behavior, workperformance, and activities of daily living).

As used herein “geroprotective activity” or “geroprotector” means abiological activity that slows down ageing and/or prolongs life and/orincreases or improves the quality of life via a decrease in the amountand/or the level of intensity of pathologies or conditions that are notlife-threatening but are associated with the aging process and which aretypical for elderly people. Pathologies or conditions that are notlife-threatening but are associated with the aging process include suchpathologies or conditions as loss of sight (cataract), deterioration ofthe dermatohairy integument (alopecia), and an age-associated decreasein weight due to the death of muscular and/or fatty cells.

As used herein, attention-deficit hyperactivity disorder (ADHD) is themost common child neuropsychiatric condition present in school-agedchildren, affecting about 5-8% of this population. ADHD refers to achronic disorder that initially manifests in childhood and ischaracterized by hyperactivity, impulsivity, and/or inattention. ADHD ischaracterized by persistent patterns of inattention and/orimpulsivity-hyperactivity that are much more extreme than is observed inindividuals at the same developmental level or stage. There isconsiderable evidence, from family and twin studies, that ADHD has asignificant genetic component. This disorder is thought to be due to aninteraction of environmental and genetic factors. ADHD includes allknown types of ADHD. For example, Diagnostic & Statistical Manual forMental Disorders (DSM-IV) identifies three subtypes of ADHD: (1) ADHD,Combined Type which is characterized by both inattention andhyperactivity-impulsivity symptoms; (2) ADHD, Predominantly InattentiveType which is characterized by inattention but nothyperactivity-impulsivity symptoms; and (3) ADHD, PredominantlyHyperactive-Impulsive Type which is characterized byHyperactivity-impulsivity but not inattention symptoms.

As used herein, attention-deficit disorder (ADD) refers to a disorder inprocessing neural stimuli that is characterized by distractibility andimpulsivity that can result in inability to control behavior and canimpair an individual's social, academic, or occupational function anddevelopment. ADD may be diagnosed by known methods, which may includeobserving behavior and diagnostic interview techniques.

As used herein “allergic disease” refers to a disorder of the immunesystem which is characterized by excessive activation of mast cells andbasophils and production of IgE immunoglobulins, resulting in an extremeinflammatory response. It represents a form of hypersensitivity to anenvironmental substance known as allergen and is an acquired disease.Common allergic reactions include eczema, hives, hay fever, asthma, foodallergies, and reactions to the venom of stinging insects such as waspsand bees. Allergic reactions are accompanied by an excessive release ofhistamines, and can thus be treated with antihistaminic agents.

As used herein, by “combination therapy” is meant a therapy thatincludes two or more different compounds. Thus, in one aspect, acombination therapy comprising a compound detailed herein and anothercompound is provided. In some variations, the combination therapyoptionally includes one or more pharmaceutically acceptable carriers orexcipients, non-pharmaceutically active compounds, and/or inertsubstances. In various embodiments, treatment with a combination therapymay result in an additive or even synergistic (e.g., greater thanadditive) result compared to administration of a single compound of theinvention alone. In some embodiments, a lower amount of each compound isused as part of a combination therapy compared to the amount generallyused for individual therapy. Preferably, the same or greater therapeuticbenefit is achieved using a combination therapy than by using any of theindividual compounds alone. In some embodiments, the same or greatertherapeutic benefit is achieved using a smaller amount (e.g., a lowerdose or a less frequent dosing schedule) of a compound in a combinationtherapy than the amount generally used for individual compound ortherapy. Preferably, the use of a small amount of compound results in areduction in the number, severity, frequency, and/or duration of one ormore side-effects associated with the compound.

As used herein, the term “effective amount” intends such amount of acompound of the invention which in combination with its parameters ofefficacy and toxicity, as well as based on the knowledge of thepracticing specialist should be effective in a given therapeutic form.As is understood in the art, an effective amount may be in one or moredoses, e.g., a single dose or multiple doses may be required to achievethe desired treatment endpoint. An effective amount may be considered inthe context of administering one or more therapeutic agents, and asingle agent may be considered to be given in an effective amount if, inconjunction with one or more other agents, a desirable or beneficialresult may be or is achieved. Suitable doses of any of theco-administered compounds may optionally be lowered due to the combinedaction (e.g., additive or synergistic effects) of the compounds.

As used herein, “unit dosage form” refers to physically discrete units,suitable as unit dosages, each unit containing a predetermined quantityof active ingredient calculated to produce the desired therapeuticeffect in association with the required pharmaceutical carrier. Unitdosage forms may contain a single or a combination therapy.

As used herein, the term “controlled release” refers to adrug-containing formulation or fraction thereof in which release of thedrug is not immediate, e.g., with a “controlled release” formulation,administration does not result in immediate release of the drug into anabsorption pool. The term encompasses depot formulations designed togradually release the drug compound over an extended period of time.Controlled release formulations can include a wide variety of drugdelivery systems, generally involving mixing the drug compound withcarriers, polymers or other compounds having the desired releasecharacteristics (e.g., pH-dependent or non-pH-dependent solubility,different degrees of water solubility, and the like) and formulating themixture according to the desired route of delivery (e.g., coatedcapsules, implantable reservoirs, injectable solutions containingbiodegradable capsules, and the like).

As used herein, by “pharmaceutically acceptable” or “pharmacologicallyacceptable” is meant a material that is not biologically or otherwiseundesirable, e.g., the material may be incorporated into apharmaceutical composition administered to a patient without causing anysignificant undesirable biological effects or interacting in adeleterious manner with any of the other components of the compositionin which it is contained. Pharmaceutically acceptable carriers orexcipients have preferably met the required standards of toxicologicaland manufacturing testing and/or are included on the Inactive IngredientGuide prepared by the U.S. Food and Drug administration.

“Pharmaceutically acceptable salts” are those salts which retain atleast some of the biological activity of the free (non-salt) compoundand which can be administered as drugs or pharmaceuticals to anindividual. A pharmaceutically acceptable salt intends ionicinteractions and not a covalent bond. As such, an N-oxide is notconsidered a salt. Such salts, for example, include: (1) acid additionsalts, formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and thelike; or formed with organic acids such as acetic acid, oxalic acid,propionic acid, succinic acid, maleic acid, tartaric acid and the like;(2) salts formed when an acidic proton present in the parent compoundeither is replaced by a metal ion, e.g., an alkali metal ion, analkaline earth metal ion, or an aluminum ion; or coordinates with anorganic base. Acceptable organic bases include ethanolamine,diethanolamine, triethanolamine and the like. Acceptable inorganic basesinclude aluminum hydroxide, calcium hydroxide, potassium hydroxide,sodium carbonate, sodium hydroxide, and the like. Further examples ofpharmaceutically acceptable salts include those listed in Berge et al,Pharmaceutical Salts, J. Pharm. Sci. 66(1):1-19, 1977. Pharmaceuticallyacceptable salts can be prepared in situ in the manufacturing process,or by separately reacting a purified compound of the invention in itsfree acid or base form with a suitable organic or inorganic base oracid, respectively, and isolating the salt thus formed during subsequentpurification. It should be understood that a reference to apharmaceutically acceptable salt includes the solvent addition forms orcrystal forms thereof, particularly solvates or polymorphs. Solvatescontain either stoichiometric or non-stoichiometric amounts of asolvent, and are often formed during the process of crystallization.Hydrates are formed when the solvent is water, or alcoholates are formedwhen the solvent is alcohol. Polymorphs include the different crystalpacking arrangements of the same elemental composition of a compound.Polymorphs usually have different X-ray diffraction patterns, infraredspectra, melting points, density, hardness, crystal shape, optical andelectrical properties, stability, and solubility. Various factors suchas the recrystallization solvent, rate of crystallization, and storagetemperature may cause a single crystal form to dominate.

The term “excipient” as used herein means an inert or inactive substancethat may be used in the production of a drug or pharmaceutical, such asa tablet containing a compound of the invention as an active ingredient.Various substances may be embraced by the term excipient, includingwithout limitation any substance used as a binder, disintegrant,coating, compression/encapsulation aid, cream or lotion, lubricant,solutions for parenteral administration, materials for chewable tablets,sweetener or flavoring, suspending/gelling agent, or wet granulationagent. Binders include, e.g., carbomers, povidone, xanthan gum, etc.;coatings include, e.g., cellulose acetate phthalate, ethylcellulose,gellan gum, maltodextrin, enteric coatings, etc.;compression/encapsulation aids include, e.g., calcium carbonate,dextrose, fructose dc (dc=“directly compressible”), honey dc, lactose(anhydrate or monohydrate; optionally in combination with aspartame,cellulose, or microcrystalline cellulose), starch dc, sucrose, etc.;disintegrants include, e.g., croscarmellose sodium, gellan gum, sodiumstarch glycolate, etc.; creams or lotions include, e.g., maltodextrin,carrageenans, etc.; lubricants include, e.g., magnesium stearate,stearic acid, sodium stearyl fumarate, etc.; materials for chewabletablets include, e.g., dextrose, fructose dc, lactose (monohydrate,optionally in combination with aspartame or cellulose), etc.;suspending/gelling agents include, e.g., carrageenan, sodium starchglycolate, xanthan gum, etc.; sweeteners include, e.g., aspartame,dextrose, fructose dc, sorbitol, sucrose dc, etc.; and wet granulationagents include, e.g., calcium carbonate, maltodextrin, microcrystallinecellulose, etc.

“Alkyl” refers to and includes saturated linear, branched, or cyclicunivalent hydrocarbon structures and combinations thereof. Particularalkyl groups are those having 1 to 20 carbon atoms (a “C₁-C₂₀ alkyl”).More particular alkyl groups are those having 1 to 8 carbon atoms (a“C₁-C₈ alkyl”). When an alkyl residue having a specific number ofcarbons is named, all geometric isomers having that number of carbonsare intended to be encompassed and described; thus, for example, “butyl”is meant to include n-butyl, sec-butyl, iso-butyl, tert-butyl andcyclobutyl; “propyl” includes n-propyl, iso-propyl and cyclopropyl. Thisterm is exemplified by groups such as methyl, t-butyl, n-heptyl, octyl,cyclohexylmethyl, cyclopropyl and the like. Cycloalkyl is a subset ofalkyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as adamantyl. A cycloalkyl comprising more than one ring maybe fused, spiro or bridged, or combinations thereof. A preferredcycloalkyl is a saturated cyclic hydrocarbon having from 3 to 13 annularcarbon atoms. A more preferred cycloalkyl is a saturated cyclichydrocarbon having from 3 to 8 annular carbon atoms (a “C₃-C₈cycloalkyl”). Examples of cycloalkyl groups include adamantyl,decahydronaphthalenyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyland the like.

“Alkylene” refers to the same residues as alkyl, but having bivalency.Examples of alkylene include methylene (—CH₂—), ethylene (—CH₂CH₂—),propylene (—CH₂CH₂CH₂—), butylene (—CH₂CH₂CH₂CH₂—) and the like.

“Alkenyl” refers to an unsaturated hydrocarbon group having at least onesite of olefinic unsaturation (i.e., having at least one moiety of theformula C═C) and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms. Examples of alkenyl include but are notlimited to —CH₂—CH═CH—CH₃ and —CH₂—CH₂-cyclohexenyl, where the ethylgroup of the latter example can be attached to the cyclohexenyl moietyat any available position on the ring. Cycloalkenyl is a subset ofalkenyl and can consist of one ring, such as cyclohexyl, or multiplerings, such as norbornenyl. A more preferred cycloalkenyl is anunsaturated cyclic hydrocarbon having from 3 to 8 annular carbon atoms(a “C₃-C₈ cycloalkenyl”). Examples of cycloalkenyl groups includecyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl and the like.

“Alkynyl” refers to an unsaturated hydrocarbon group having at least onesite of acetylenic unsaturation (i.e., having at least one moiety of theformula and preferably having from 2 to 10 carbon atoms and morepreferably 2 to 8 carbon atoms and the like.

“Substituted alkyl” refers to an alkyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkenyl” refers to alkenyl group having from 1 to 5substituents including, but not limited to, substituents such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, aminosulfonyl,sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy and the like.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, cycloalkyl-C(O)—,substituted cycloalkyl-C(O)—, alkynyl-C(O)—, substituted alkynyl-C(O)—,aryl-C(O)—, substituted aryl-C(O)—, heteroaryl-C(O)—, substitutedheteroaryl-C(O)—, heterocyclic-C(O)—, and substitutedheterocyclic-C(O)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Acyloxy” refers to the groups H—C(O)O—, alkyl-C(O)O—, substitutedalkyl-C(O)O—, alkenyl-C(O)O—, substituted alkenyl-C(O)O—,alkynyl-C(O)O—, substituted alkynyl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—,heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—, heterocyclic-C(O)O—,and substituted heterocyclic-C(O)O—, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Heterocycle”, “heterocyclic”, or “heterocyclyl” refers to a saturatedor an unsaturated non-aromatic group having a single ring or multiplecondensed rings, and having from 1 to 10 annular carbon atoms and from 1to 4 annular heteroatoms, such as nitrogen, sulfur or oxygen, and thelike. A heterocycle comprising more than one ring may be fused, Spiro orbridged, or any combination thereof. In fused ring systems, one or moreof the rings can be aryl or heteroaryl. A heterocycle having more thanone ring where at least one ring is aromatic may be connected to theparent structure at either a non-aromatic ring position or at anaromatic ring position. In one variation, a heterocycle having more thanone ring where at least one ring is aromatic is connected to the parentstructure at a non-aromatic ring position.

“Substituted heterocyclic” or “substituted heterocyclyl” refers to aheterocycle group which is substituted with from 1 to 3 substituentsincluding, but not limited to, substituents such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like. In one variation, a substitutedheterocycle is a heterocycle substituted with an additional ring,wherein the additional ring may be aromatic or non-aromatic.

“Aryl” or “Ar” refers to an unsaturated aromatic carbocyclic grouphaving a single ring (e.g., phenyl) or multiple condensed rings (e.g.,naphthyl or anthryl) which condensed rings may or may not be aromatic.In one variation, the aryl group contains from 6 to 14 annular carbonatoms. An aryl group having more than one ring where at least one ringis non-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, an aryl group having more than one ring where at least onering is non-aromatic is connected to the parent structure at an aromaticring position.

“Heteroaryl” or “HetAr” refers to an unsaturated aromatic carbocyclicgroup having from 1 to 10 annular carbon atoms and at least one annularheteroatom, including but not limited to heteroatoms such as nitrogen,oxygen and sulfur. A heteroaryl group may have a single ring (e.g.,pyridyl, furyl) or multiple condensed rings (e.g., indolizinyl,benzothienyl) which condensed rings may or may not be aromatic. Aheteroaryl group having more than one ring where at least one ring isnon-aromatic may be connected to the parent structure at either anaromatic ring position or at a non-aromatic ring position. In onevariation, a heteroaryl group having more than one ring where at leastone ring is non-aromatic is connected to the parent structure at anaromatic ring position.

“Substituted aryl” refers to an aryl group having 1 to 5 substituentsincluding, but not limited to, groups such as alkoxy, substitutedalkoxy, acyl, acyloxy, carbonylalkoxy, acylamino, substituted orunsubstituted amino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aryl, substituted aryl, heteroaryl, substituted heteroaryl, aryloxy,substituted aryloxy, cyano, halo, hydroxyl, nitro, carboxyl, thiol,thioalkyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted aralkyl,aminosulfonyl, sulfonylamino, sulfonyl, oxo, carbonylalkylenealkoxy andthe like.

“Substituted heteroaryl” refers to a heteroaryl group having 1 to 5substituents including, but not limited to, groups such as alkoxy,substituted alkoxy, acyl, acyloxy, carbonylalkoxy, acylamino,substituted or unsubstituted amino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, aryloxy, substituted aryloxy, cyano, halo, hydroxyl, nitro,carboxyl, thiol, thioalkyl, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, aminosulfonyl, sulfonylamino, sulfonyl, oxo,carbonylalkylenealkoxy and the like.

“Aralkyl” refers to a residue in which an aryl moiety is attached to analkyl residue and wherein the aralkyl group may be attached to theparent structure at either the aryl or the alkyl residue. Preferably, anaralkyl is connected to the parent structure via the alkyl moiety. Inone variation, an aralkyl is a fused ring system where at least onecycloalkyl moiety is fused with at least one aryl moiety. A “substitutedaralkyl” refers to a residue in which an aryl moiety is attached to asubstituted alkyl residue and wherein the aralkyl group may be attachedto the parent structure at either the aryl or the alkyl residue. When anaralkyl is connected to the parent structure via the alkyl moiety, itmay also be referred to as an “alkaryl”. More particular alkaryl groupsare those having 1 to 3 carbon atoms in the alkyl moiety (a “C₁-C₃alkaryl”).

“Alkoxy” refers to the group alkyl-O—, which includes, by way ofexample, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy,sec-butoxy, n-pentoxy, n-hexoxy, 1,2-dimethylbutoxy, and the like.Similarly, alkenyloxy refers to the group “alkenyl-O—” and alkynyloxyrefers to the group “alkynyl-O—”. “Substituted alkoxy” refers to thegroup substituted alkyl-O.

“Unsubstituted amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR_(a)R_(b), where either (a)each R_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, substituted heterocyclic, providedthat both R_(a) and R_(b) groups are not H; or (b) R_(a) and R_(b) arejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Acylamino” refers to the group —C(O)NR_(a)R_(b) where R_(a) and R_(b)are independently selected from the group consisting of H, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl,heterocyclic, substituted heterocyclic or R_(a) and R_(b) groups can bejoined together with the nitrogen atom to form a heterocyclic orsubstituted heterocyclic ring.

“Aminoacyl” refers to the group NR_(a)C(O)R_(b) where each R_(a) andR_(b) group is independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic or substituted heterocyclic. Preferably, R_(a)is H or alkyl.

“Aminosulfonyl” refers to the groups —NRSO₂-alkyl, —NRSO₂ substitutedalkyl, —NRSO₂-alkenyl, —NRSO₂-substituted alkenyl, —NRSO₂-alkynyl,—NRSO₂-substituted alkynyl, —NRSO₂-cycloalkyl, —NRSO₂-substitutedcycloalkyl, —NRSO₂-aryl, —NRSO₂-substituted aryl, —NRSO₂-heteroaryl,—NRSO₂-substituted heteroaryl, —NRSO₂-heterocyclic, and—NRSO₂-substituted heterocyclic, where R is H or alkyl and whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the groups —SO₂NH₂, —SO₂NR-alkyl,—SO₂NR-substituted alkyl, —SO₂NR-alkenyl, —SO₂NR-substituted alkenyl,—SO₂NR-alkynyl, —SO₂NR-substituted alkynyl, —SO₂NR-aryl,—SO₂NR-substituted aryl, —SO₂NR-heteroaryl, —SO₂NR-substitutedheteroaryl, —SO₂NR-heterocyclic, and —SO₂NR-substituted heterocyclic,where R is H or alkyl, or —SO₂NR₂, where the two R groups are takentogether and with the nitrogen atom to which they are attached to form aheterocyclic or substituted heterocyclic ring.

“Sulfonyl” refers to the groups —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-alkynyl, —SO₂-substitutedalkynyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic.

“Aminocarbonylalkoxy” refers to the group —NR_(a)C(O)OR_(b) where eachR_(a) and R_(b) group is independently selected from the groupconsisting of H, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic and substituted heterocyclyl.

“Carbonylalkylenealkoxy” refers to the group —C(═O)—(CH₂)_(n)—OR where Ris a substituted or unsubstituted alkyl and n is an integer from 1 to100, more preferably n is an integer from 1 to 10 or 1 to 5.

“Halo” or “halogen” refers to elements of the Group 17 series havingatomic number 9 to 85. Preferred halo groups include the radicals offluorine, chlorine, bromine and iodine. Where a residue is substitutedwith more than one halogen, it may be referred to by using a prefixcorresponding to the number of halogen moieties attached, e.g.,dihaloaryl, dihaloalkyl, trihaloaryl etc., refer to aryl and alkylsubstituted with two (“di”) or three (“tri”) halo groups, which may bebut are not necessarily the same halogen; thus 4-chloro-3-fluorophenylis within the scope of dihaloaryl. An alkyl group in which each H isreplaced with a halo group is referred to as a “perhaloalkyl.” Apreferred perhaloalkyl group is trifluoroalkyl (—CF₃). Similarly,“perhaloalkoxy” refers to an alkoxy group in which a halogen takes theplace of each H in the hydrocarbon making up the alkyl moiety of thealkoxy group. An example of a perhaloalkoxy group is trifluoromethoxy(—OCF₃).

“Carbonyl” refers to the group C═O.

“Cyano” refers to the group —CN.

“Oxo” refers to the moiety ═O.

“Nitro” refers to the group —NO₂.

“Thioalkyl” refers to the groups —S-alkyl.

“Alkylsulfonylamino” refers to the groups —R¹SO₂NR_(a)R_(b) where R_(a)and R_(b) are independently selected from the group consisting of H,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, or the R_(a) andR_(b) groups can be joined together with the nitrogen atom to form aheterocyclic or substituted heterocyclic ring and R¹ is an alkyl group.

“Carbonylalkoxy” refers to as used herein refers to the groups—C(O)O-alkyl, —C(O)O-substituted alkyl, —C(O)O-aryl, —C(O)O-substitutedaryl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl, —C(O)O-alkynyl,—C(O)O-substituted alkynyl, —C(O)O-heteroaryl, —C(O)O-substitutedheteroaryl, —C(O)O-heterocyclic or —C(O)O-substituted heterocyclic.

“Geminal” refers to the relationship between two moieties that areattached to the same atom. For example, in the residue —CH₂—CHR¹R², R¹and R² are geminal and R¹ may be referred to as a geminal R group to R².

“Vicinal” refers to the relationship between two moieties that areattached to adjacent atoms. For example, in the residue —CHR¹—CH₂R², R¹and R² are vicinal and R¹ may be referred to as a vicinal R group to R².

A composition of “substantially pure” compound means that thecomposition contains no more than 15% or preferably no more than 10% ormore preferably no more than 5% or even more preferably no more than 3%and most preferably no more than 1% impurity, which impurity may be thecompound in a different stereochemical form. For instance, a compositionof substantially pure (S) compound means that the composition containsno more than 15% or no more than 10% or no more than 5% or no more than3% or no more than 1% of the (R) form of the compound.

Compounds of the Invention

Compounds according to the invention are detailed herein, including inthe Brief Summary of the Invention and elsewhere. The invention includesthe use of all of the compounds described herein, including any and allstereoisomers, including geometric isomers (cis/trans or E/Z isomers),salts and solvates of the compounds described herein, as well as methodsof making such compounds.

In one aspect, compounds of the formula (IA) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl, S(O)-aralkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety, or is taken together        with a vicinal R^(8(a-h)) and the carbon atoms to which they are        attached to form a substituted or unsubstituted C₃-C₈        cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, or        substituted or unsubstituted heterocyclyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In one variation, compounds of the formula (IA) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

each R^(4a) and R^(1b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(2a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b)) are taken together with the carbon to which they are attachedto form a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations, compounds of the formula (IA), and salts andsolvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano,alkynyl, acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b); oramino substituted with one or two substituted or unsubstituted C₁-C₈alkyl; and

(2) when each m, n, o and p is 0 and R⁵ is methyl, then Q is substitutedor unsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula—CR⁹═CR^(10a)R^(10b), or amino substituted with one or two substitutedor unsubstituted C₁-C₈ alkyl;

(3) wherein at least one of m, n, o and p is 1 and R⁵ is H, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, aminoacyl, acyloxy,carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(4) wherein at least one of m, n, o and p is 1 and R⁵ is methyl, then Qsubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl other than a substituted piperazinyl, aminoacyl, acyloxy,carboxyl, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is a groupof the formula —CR⁹═CR^(10a)R^(10b), or amino substituted with one ortwo substituted or unsubstituted C₁-C₈ alkyl.

In one variation, compounds of the formula (IA), and salts and solvatesthereof, are embraced, provided that when none of R¹, R^(2a), R^(2b),R^(3a), R^(3b), R^(4a) and R^(4b) are taken together to form a ring, atleast one of m, n, o and p is 1 and each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, alkoxy,halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety, then:

(i) when Q is a carbonylalkoxy of the formula —COOCH₃ and R⁵ is anunsubstituted C₁-C₈ alkyl where the unsubstituted C₁-C₈ alkyl is methyl,then one or more of provisions (a)-(d) apply: (a) at least one of X¹, X²and X³ is N or CR⁶; (b) R^(2a) and R^(2b) are both H; (c) R¹ is H or anunsubstituted C₁-C₈ alkyl; and (d) R⁵ is H;(ii) when either (1) Q is carbonylalkoxy of the formula —COOCH₃ or—COOCH₂CH₃ or (2) Q is an alkoxy of formula —OCH₃ or —OCH₂CH₃ and isbound to a carbonyl group to form a moiety of the formula —COOCH₃ or—COOCH₂CH₃, then one or more of provisions (a)-(c) apply: (a) at leastone of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ where R⁶ ismethyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is anunsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, o and p is 1;(iii) when either (1) Q is an acylamino of the formula —CONH₂ or (2) Qis an unsubstituted amino bound to a carbonyl group to form a moiety ofthe formula —CONH₂, then one or more of provisions (a)-(e) apply: (a) atleast one of X¹, X² and X³ is N or CR⁶, provided that if X² is CR⁶ whereR⁶ is methyl, then R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R⁵ is anunsubstituted C₂-C₈ alkyl; (c) R⁵ and R¹ are independently anunsubstituted C₁-C₈ alkyl; (d) at least one of n, m, o and p is 1; and(e) when R⁵ is an unsubstituted C₁-C₈ alkyl, then R^(2a) and R^(2b) areboth H;(iv) when Q is cyano, then one or more of provisions (a)-(d) apply: (a)at least one of X¹, X² and X³ is N or CR⁶; (b) R^(2a) and R^(2b) areboth H; (c) R¹ is an unsubstituted C₁-C₈ alkyl; and (d) at least one ofn, m, o and p is 1;(v) when Q is an acyloxy of the formula —COOH, then one or more ofprovisions (a)-(c) apply: (a) at least one of X¹, X² and X³ is N or CR⁶;(b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) at least one of n, m, oand p is 1;(vi) when Q is an acyloxy of the formula —COO-substituted alkyl, thenone or more of provisions (a)-(c) apply: (a) at least one of X¹, X² andX³ is N or CR⁶; (b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ isother than H.

In one variation, provided is a compound of the formula (IA) where atleast one of X¹, X² and X³ is CH or CR⁶. In another variation, at leastone of X¹, X² and X³ is N. In another variation, one of X¹, X² and X³ isN. In one variation, X¹ is N and each X² and X³ is independently CH orCR⁶. In another variation, X² is N and each X¹ and X³ is independentlyCH or CR⁶. In yet another variation, X³ is N and each X¹ and X² isindependently CH or CR⁶. In another variation, two of X¹, X² and X³ isN. In one variation, each X¹ and X³ is N and X² is CH or CR⁶.

In another aspect of the invention, compounds of the formula (IB) areprovided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(2a) and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(4a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety ora butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R^(2a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aralkyl,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In one variation, compounds of the formula (IB) are provided:

or a salt or solvate thereof; wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy, or R¹ and R^(2a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R¹ and R^(3a) are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ andR^(4a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety;

each R^(2a) and R^(2b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(2a) and R^(2b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(2a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(2a) and R^(3a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(2a) andR^(4a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety;

each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(3a) and R^(3b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(3a) and R¹ are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety, or R^(3a) and R^(2a) are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(3a) andR^(4a) are taken together to form a propylene (—CH₂CH₂CH₂—) moiety or abutylene (—CH₂CH₂CH₂CH₂—) moiety;

each R^(4a) and R^(4b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, nitro, substituted or unsubstituted amino,hydroxyl, alkoxy, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(4a) and R^(4b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(4a) and R¹ are taken together to form an ethylene(—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety, or R^(4a) andR^(2a) are taken together to form a methylene (—CH₂—) moiety or anethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are taken together toform a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each m, n, o or p is independently 0 or 1;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations, compounds of the formula (IB), and salts andsolvates thereof, are embraced, provided that:

(1) when each m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, cyano, alkynyl, aminocarbonylalkoxy,acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), or aminosubstituted with one or two substituted or unsubstituted C₁-C₈ alkyl;

(2) when each m, n, o and p is 0 and R⁵ is unsubstituted C₁-C₈ alkyl,then Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino,aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b); and

(3) when at least one of m, n, o and p is 1 and R⁵ is H, then Q issubstituted or unsubstituted aryl other than unsubstituted phenyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, substituted amino, aminoacyl,acyloxy, cyano, alkynyl, aminocarbonylalkoxy, or is a group of theformula —CR⁹═CR^(10a)R^(10b).

In one variation, compounds of the formula (IB), and salts and solvatesthereof, are embraced, provided that:

(i) when m, n, o and p are each 0 and Q is a substituted aryl whereinthe substituted aryl is a carboline moiety, then one or more ofprovisions (a)-(c) apply: (a) X¹, X² and X³ are independently N or CH;(b) R⁵ is an unsubstituted C₁-C₈ alkyl; and (c) R¹ is an unsubstitutedC₁-C₈ alkyl;(ii) when none of R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b)are aken together to form a ring, at least one of m, n, o and p is 1 andeach R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, or is taken together with a geminal R^(8(a-h))to form a substituted or unsubstituted methylene moiety or is takentogether with a geminal R^(8(a-h)) and the carbon to which they areattached to form a carbonyl moiety, then:

(A) when Q is a carboxyl moiety, then one or more of provisions (a)-(e)apply: (a) at least one of X¹, X² and X³ is independently N or CR⁶; (b)two or more of m, n, o and p are 1; (c) at least one of R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) is other than H; (d)when R⁵ is an unsubstituted C₁-C₈ alkyl then at least one of m, n, o andp is 1; and (e) when R⁵ is H then R^(2a) and R^(2b) are each H;

(B) when one of R^(2a) and R^(2b) is methyl or when R^(2a) and R^(2b)are taken together to form a carbonyl, then one or more of provisions(a)-(c) apply: (a) R⁵ is an unsubstituted C₁-C₈ alkyl; (b) R¹ is anunsubstituted C₁-C₈ alkyl; and (c) Q is a substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, aminoacyl, cyano,alkynyl, aminocarbonylalkoxy; and

(C) when R¹ and R^(2a) are taken together to form a butylene(—CH₂CH₂CH₂CH₂—), then one or more of provisions (a)-(d) apply: (a) R⁵is an unsubstituted C₁-C₈ alkyl; (b) the 6-membered ring formed when R¹and R^(2a) are taken together to form a butylene (—CH₂CH₂CH₂CH₂—) moietyis not further substituted with a cyclic structure and is notsubstituted with an alkenyl or cyano-containing moiety; (c) X³ is CH andX¹ and X² are independently N or CR⁶; and (d) Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy or acylamino moiety.

In one variation, provided is a compound of the formula (IB) where atleast one of X¹l, X² and X³ is CH or CR⁶. In another variation, at leastone of X¹, X² and X³ is N. In another variation, one of X¹, X² and X³ isN. In one variation, X¹ is N and each X² and X³ is independently CH orCR⁶. In another variation, X² is N and each X¹ and X³ is independentlyCH or CR⁶. In yet another variation, X³ is N and each X¹ and X² isindependently CH or CR⁶. In another variation, two of X¹, X² and X³ isN. In one variation, each X¹ and X³ is N and X² is CH or CR⁶.

In another aspect, the invention provides a method of treating acognitive disorder, psychotic disorder, neurotransmitter-mediateddisorder or a neuronal disorder in an individual comprisingadministering to an individual in need thereof an effective amount of acompound of any formulae detailed herein, such as a compound of formula(IA), (IB), (IA1), (IA2), (IA3), (A1) to (A5), (B1) to B(10), (C1), to(C5), (J-1) to (J-5), (J-1a) to (J5a), (J-1b), (J-1c), (J-1d), (K-1) to(K-5), or (K-1a) to (K-5a), or a salt or solvate thereof.

In one variation, compounds are provided, wherein the chain comprisingR^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g), R^(8h) and Q isselected from the following structures:

or a salt or solvate thereof, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g), R^(8h) and Q are defined as for formula (IA) or(IB) and ring A comprises a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl group.

In another variation, compounds of formula (IA) or (IB) are provided,wherein the chain comprising R^(8a), R^(8b), R^(8c), R^(8d), R^(8e),R^(8f), R^(8g), R^(8h) and Q is selected from the following structures:

or a salt or solvate thereof, wherein R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g), R^(8h) and Q are defined as for formula (IA) or(IB) and ring A comprises a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl group. In a particularvariation, when o and p are each 0, the chain comprising R^(8a), R^(8b),R^(8c), R^(8d), and Q is selected from the following structures:

In a particular variation, where ring A depicted above comprises asubstituted or unsubstituted C₃-C₈ cycloalkenyl, the double-bond of thecycloalkenyl ring is at a position other than in the linear chain. Forexample, if the carbon atoms bearing R^(8a) and R^(8c) are part of asubstituted or unsubstituted C₃-C₈ cycloalkenyl ring, e.g., ring Adepicted above, then the carbon atoms bearing R^(8a) and R^(8c) areconnected by a single bond.

When Q is an unsubstituted or substituted heteroaryl, in one variationit is a heteroaryl containing an annular nitrogen atom. In one aspect,when Q is an unsubstituted or substituted heteroaryl the heteroarylcontains only nitrogen and carbon annular atoms. In a particularvariation, Q is an unsubstituted pyridyl that may be bound to Q at anyavailable ring position. For example, in one variation of formulae (IA)and (IB), Q is 4-pyridyl, 3-pyridyl or 2-pyridyl. When Q is asubstituted heteroaryl in one aspect it is a substituted pyridyl. When Qis a substituted pyridyl, the pyridyl may be substituted with one ormore than one substituent and the substituted pyridyl may be bound tothe parent structure at any available ring position. For example, in onevariation of formulae (IA) and (IB), Q is a mono-substituted pyridylwhere the substituent is a C₁-C₈ unsubstituted alkyl (e.g., methyl).

In another variation, the compound is of formulae (IA) and (IB) where Qis a di- or tri-substituted aryl, substituted heteroaryl, substituted orunsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl orsubstituted or unsubstituted heterocyclyl. In one aspect, the compoundis of formulae (IA) and (IB) where Q is a di- or tri-substituted aryl.When Q is a di- or tri-substituted aryl, the substituents may be thesame or different and may be located at any available position on thearyl ring. In one aspect, Q is a di- or tri-substituted phenyl (e.g.,4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl,3,4-dichlorophenyl, 3-chloro-4-fluorophenyl, 2,4-difluorophenyl,2,4-dichlorophenyl and 2,4,6-trifluorophenyl). In another aspect, Q is aphenyl substituted with at least one chloro or methyl group (e.g.,4-chlorophenyl and 4-methylphenyl). In yet another aspect, the compoundis of formulae (IA) and (IB) where Q is a substituted heteroaryl (e.g.,where Q is 6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl or pyrimidinyl). In one aspect, Q is asubstituted pyridyl such as 6-methyl-3-pyridyl,6-trifluoromethyl-3-pyridyl and 5-trifluoromethyl-3-pyridyl.

In one variation, the compound is of formulae (IA) and (IB) where atleast one of X¹-X³ is CR⁶ where R⁶ is chloro. In such variation, X² isCR⁶ where R⁶ is chloro. In another variation, X² is CR⁶, and X¹ and X³are each CH.

In specific variations, compounds of formula (IA) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, X¹, X², X³,R^(8(a-h)), m, n, o, p and Q are defined as for formula (IA) and, whereapplicable, any variation thereof detailed herein. That is, variationsof formula (IA) detailed throughout, where applicable, apply equally toany of formulae (IA1)-(IA3) the same as if each and every variation werespecifically and individually listed for formulae (IA1)-(IA3).Pharmaceutically acceptable salts of compounds of formulae (IA1)-(IA3)are also provided.

In some variations of formula (IA1), at least one of X¹, X² and X³ is CHor CR⁶. In another variation, at least one of X¹, X² and X³ is N. Inanother variation, one of X¹, X² and X³ is N. In one variation, X¹ is Nand each X² and X³ is independently CH or CR⁶. In another variation, X²is N and each X¹ and X³ is independently CH or CR⁶. In yet anothervariation, X³ is N and each X¹ and X² is independently CH or CR⁶. Inanother variation, two of X¹, X² and X³ is N. In one variation, each X¹and X³ is N and X² is CH or CR⁶.

In one variation of formula (IA2), X² is CH or CR⁶ where R⁶ is halo orsubstituted or unsubstituted C₁-C₈ alkyl. In a particular variation offormula (IA2), X² is CR⁶ where R⁶ is halo (e.g., chloro). In anotherparticular variation of formula (IA2), X² is CR⁶ where R⁶ isunsubstituted C₁-C₈ alkyl (e.g., methyl). In a particular variation offormula (IA2), X² is CH. In further variations of formula (IA2), Q is asubstituted or unsubstituted heteroaryl. In one variation, Q is anunsubstituted heteroaryl (e.g., 4-pyridyl or 4-pyrimidyl). In stillfurther variations of formula (IA2), X² is CH or CR⁶ where R⁶ is halo orsubstituted or unsubstituted C₁-C₈ alkyl and Q is a substituted orunsubstituted heteroaryl. In one aspect of formula (IA2), X² is CR⁶where R⁶ is a C₁-C₈ alkyl (e.g., methyl) and Q is a substituted orunsubstituted heteroaryl. In another aspect of formula (IA2), X² is CR⁶where R⁶ is halo (e.g., chloro) and Q is a substituted or unsubstitutedheteroaryl. In another aspect of formula (IA2), X² is CH and Q is asubstituted or unsubstituted heteroaryl. In a further aspect of formula(IA2), X² is CH or CR⁶ where R⁶ is methyl or chloro and Q is 4-pyridyl.

In one variation, compounds of the formula (IA3) are provided, or a saltor solvate thereof, where R¹ is a substituted or unsubstituted C₁-C₈alkyl; R⁶ is H, halo, trifluoromethyl, a C₁-C₈ unsubstituted alkyl or asubstituted amino; and Q is substituted aryl or a substituted orunsubstituted heteroaryl. In one variation of formula (IA3), R¹ is anunsubstituted C₁-C₈ alkyl or a C₁-C₈ alkyl substituted with a halo orhydroxyl group. In one such variation, R¹ is methyl, 2-haloethyl (e.g.,2-fluoroethyl), 2,2,2-trifluoroethyl, or a hydroxyl-substituted pentylgroup. In a particular variation of formula (IA3), R¹ is —CH₃, —CH₂CH₂F,—CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH. In another variation of formula (IA3), R⁶is H, halo, methyl, trifluoromethyl, or a substituted amino of theformula —N(H)(C₁-C₈ unsubstituted alkyl). When R⁶ is a halo (e.g.,fluoro or chloro), in one aspect R⁶ is chloro. In one variation offormula (IA3), R⁶ is H, methyl or chloro. In one variation of formula(IA3), R⁶ is methyl or chloro. When R⁶ is a substituted amino of theformula —N(H)(C₁-C₈ unsubstituted alkyl), in one aspect C₁-C₈unsubstituted alkyl is a linear C₁-C₈ unsubstituted alkyl such as methylor ethyl. In a particular variation of formula (IA3), R⁶ is —N(H)(CH₃).It is understood that any R¹ for formula (IA3) may be combined with anyR⁶ of formula (IA3) the same as if each and every combination werespecifically and individually listed. For example, compounds of theformula (IA3) are provided where R¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or—CH₂CH₂C(CH₃)₂OH and R⁶ is H, chloro, fluoro, methyl, trifluoromethyl,or —N(H)(CH₃). Likewise, compounds of the formula (IA3) are providedwhere R¹ is methyl and R⁶ is H, halo, methyl or a substituted amino ofthe formula —N(H)(C₁-C₈ unsubstituted alkyl). In one such aspect,compounds of the formula (IA3) are provided where R¹ is methyl and R⁶ isH, halo or methyl. In one such aspect, compounds of the formula (IA3)are provided where R¹ is methyl and R⁶ is halo (e.g., fluoro or chloro),trifluoromethyl, or methyl. When each Q of formula (IA3) isindependently a substituted aryl, in one aspect Q is a substitutedphenyl. In one aspect, Q is a mono-substituted phenyl. In a particularaspect, each Q of formula (IA3) is independently a halo-substitutedphenyl, alkoxy-substituted phenyl or an acylamino-substituted phenyl.Thus, compounds of the formula (IA3) are provided where each Q in onevariation is independently a phenyl mono-substituted with a fluoro,C₁-C₈ alkoxy (e.g., methoxy), an acylamino moiety of the formula—C(O)NH(C₁-C₈ unsubstituted alkyl) or an acylamino moiety of the formula—C(O)N(C₁-C₈ unsubstituted alkyl)₂, such as 2-fluoro-phenyl,4-fluoro-phenyl, 4-methoxy-phenyl, 4-(C(O)NH(CH₃) and4-(C(O)N(CH₃)₂)-phenyl. In one aspect, Q is a di-substituted phenyl. Inone aspect, each Q of formula (IA3) is independently a di-halosubstituted phenyl group such as 3,4-difluoro-phenyl. In a particularaspect, each Q of formula (IA3) is independently a phenyl groupsubstituted with one halo group and one C₁-C₈ alkoxy group (e.g.,methoxy). Thus, compounds of the formula (IA3) are provided where each Qin one variation is independently a phenyl substituted with a fluoro anda C₁-C₈ alkoxy group, such as 3-fluoro-4-methoxy-phenyl. When each Q offormula (IA3) is independently a substituted or unsubstitutedheteroaryl, in one variation the substituted or unsubstituted heteroarylis a pyridyl or pyrimidyl moiety. Thus, in one aspect of formula (IA3),Q is an unsubstituted pyridyl or pyrimidyl, such as 3-pyridyl, 4-pyridyland 4-pyrimidyl. In another aspect of formula (IA3), Q is a substitutedpyridyl, such as 6-methyl-3-pyridyl. It is understood that any Q forformula (IA3) may be combined with any R¹ and/or R⁶ of formula (IA3) thesame as if each and every combination were specifically and individuallylisted. For example, compounds of the formula (IA3) are provided whereR¹ is —CH₃, —CH₂CH₂F, —CH₂CF₃, or —CH₂CH₂C(CH₃)₂OH; R⁶ is H, chloro,fluoro, methyl, trifluoromethyl, or —N(H)(CH₃) and Q is 4-pyridyl,3-pyridyl, 6-methyl-3-pyridyl, 6-pyrimidyl, 4-fluoro-phenyl,4-methoxy-phenyl, 3-fluoro-4-methoxy-phenyl or4-dimethylcarbamoyl-phenyl. Likewise, compounds of the formula (IA3) areprovided where R¹ is methyl; R⁶ is H, halo or methyl and Q is anunsubstituted pyridyl.

All variations referring to the formulae herein, such as formulae (IA),(IA1), (IA2) and (IA3), where applicable, may apply to formula (IB), thesame as if each and every variation were specifically and individuallylisted.

In specific variations, compounds of formula (IA) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X², X³, R^(8(a-h)) andQ, where present, are defined herein and, where applicable, anyvariation thereof detailed herein. That is, variations of the formula(IA) detailed throughout, where applicable, apply equally to any offormulae (A1)-(A5) the same as if each and every variation werespecifically and individually listed for formulae (A1)-(A5). In oneaspect of this invention, at least one of X¹, X² and X³ is CH or CR⁶. Inanother variation, at least one of X¹, X² and X³ is N. In another aspectof this invention, at least two of X¹, X² and X³ are N. In anotheraspect of this variation, both X¹ and X³ are N, and X² is CR⁶, where R⁶is as defined herein. Pharmaceutically acceptable salts of compounds offormulae (A1)-(A5) are also provided.

In some variations of formulae (A1)-(A5), at least one of X¹, X² and X³is CH or CR⁶. In another variation, at least one of X¹, X² and X³ is N.In another variation, one of X′, X² and X³ is N. In one variation, X¹ isN and each X² and X³ is independently CH or CR⁶. In another variation,X² is N and each X¹ and X³ is independently CH or CR⁶. In yet anothervariation, X³ is N and each X¹ and X² is independently CH or CR⁶. Inanother variation, two of X¹, X² and X³ is N. In one variation, each X¹and X³ is N and X² is CH or CR⁶.

All variations referring to formula (IA), such as formulae (A1)-(A5),where applicable, may apply to formula (IB), the same as if each andevery variation were specifically and individually listed.

In another variation, compounds of formula (IA) have the structure:

or a salt or solvate thereof; wherein R⁵, X¹, X², X³, R^(8(a-h)) and Q,where present, are defined herein and, where applicable, any variationthereof detailed herein. That is, variations of the formula (IA)detailed throughout, where applicable, apply equally to any of formulae(B1)-(B10) the same as if each and every variation were specifically andindividually listed for formulae (B1)-(B10). In one embodiment,compounds of the formula (IA) are provided wherein the compounds are ofthe formula (B1)-(B10) except that, instead of R¹ of formula (IA) beingtaken together with R^(2a) of formula (IA) to provide compounds of theformula (B1)-(B10), R¹ is taken together with R^(3a) to form a propylenemoiety or a butylene moiety. In another embodiment, compounds of theformula (IA) are provided wherein the compounds are of the formula(B1)-(B10) except that, instead of R¹ of formula (IA) being takentogether with R^(2a) of formula (IA) to provide compounds of the formula(B1)-(B10), R¹ is taken together with R^(4a) to form an ethylene moietyor a propylene moiety. In a further embodiment, compounds of the formula(IA) are provided wherein the compounds are of the formula (B 1)-(B10)except that, instead of R¹ of formula (IA) being taken together withR^(2a) of formula (IA) to provide compounds of the formula (B1)-(B10),R^(2a) and R^(3a) are taken together to form an ethylene moiety or apropylene moiety. In still a further embodiment, compounds of theformula (IA) are provided wherein the compounds are of the formula(B1)-(B10) except that, instead of R¹ of formula (IA) being takentogether with R^(2a) of formula (IA) to provide compounds of the formula(B1)-(B10), R^(2a) and R^(4a) are taken together to form a methylenemoiety or an ethylene moiety. In yet another embodiment, compounds ofthe formula (IA) are provided wherein the compounds are of the formula(B1)-(B10) except that, instead of R¹ of formula (IA) being takentogether with R^(2a) of formula (IA) to provide compounds of the formula(B1)-(B10), R^(3a) and R^(4a) are taken together to form a propylenemoiety or a butylene moiety. Variations detailed throughout, whereapplicable, apply to such formulae the same as if each and everyvariation were specifically and individually listed. Pharmaceuticallyacceptable salts of such formulae are also provided. In one aspect ofthis invention, at least one of X¹, X² and X³ is N. In another aspect ofthis invention, at least two of X¹, X² and X³ are N. In another aspectof this variation, both X¹ and X³ are N, and X² is CR⁶, where R⁶ is asdefined herein. Pharmaceutically acceptable salts of compounds offormulae (A1)-(A5) are also provided.

In some variations of formulae (B1)-(B10), at least one of X¹, X² and X³is CH or CR⁶. In another variation, at least one of X¹, X² and X³ is N.In another variation, one of X¹, X² and X³ is N. In one variation, X¹ isN and each X² and X³ is independently CH or CR⁶. In another variation,X² is N and each X¹ and X³ is independently CH or CR⁶. In yet anothervariation, X³ is N and each X¹ and X² is independently CH or CR⁶. Inanother variation, two of X¹, X² and X³ is N. In one variation, each X¹and X³ is N and X² is CH or CR⁶.

All variations referring to formula (IA), such as formulae (B1)-(B10),where applicable, may apply to formula (IB), the same as if each andevery variation were specifically and individually listed.

In another variation, compounds of formula (IA) have the structures(C1)-(C5):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8c) is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^(8d) is H or substituted or unsubstituted C₁-C₈ alkyl, and the

bond indicates the presence of either an E or Z double bondconfiguration;

Y is O or NR¹¹;

each R¹¹, R^(12a) and R^(12b) is independently H or substituted orunsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, the compound is of the formula (C1):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8c) is H, OH or substituted or unsubstituted C₁-C₈ alkyl;

R^(8d) is H or substituted or unsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, the compound is of the formula (C2):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

R^(8d) is H or substituted or unsubstituted C₁-C₈ alkyl, and the

bond indicates the presence of either an E or Z double bondconfiguration;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, the compound is of the formula (C3):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, the compound is of the formula (C4):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

Y is O or NR¹¹;

each R¹¹, R^(12a) and R^(12b) is independently H or substituted orunsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some embodiments, the compound is of the formula (C5):

or a salt or solvate thereof, wherein:

R¹ is H or substituted or unsubstituted C₁-C₈ alkyl;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

R⁶ is H, halo, or substituted or unsubstituted C₁-C₈ alkyl;

each X¹ and X³ is independently CH or N; and

D is substituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.

In some variations of the formula (C5), D is substituted aryl,unsubstituted aryl other than unsubstituted phenyl, or substituted orunsubstituted heteroaryl.

In some variations of the formulae (C1)-(C5), R¹ is H or unsubstitutedC₁-C₈ alkyl (e.g., methyl). In some variations, R¹ is methyl. In somevariations of the formulae (C1)-(C5), each X¹ and X³ is CH. In somevariations of the formulae (C1)-(C5), one of X¹ and X³ is CH and theother is N. In some variations, X¹ is CH. In some variations, X³ is CH.In some variations, X¹ is N. In some variations, X³ is N. In somevariations of the formulae (C1)-(C5), each X¹ and X³ is N. In somevariations of the formulae (C1)-(C5), R⁶ is H, chloro or methyl. In somevariations of the formulae (C1)-(C5), R⁶ is H. In some variations of theformulae (C1)-(C5), R⁶ is chloro. In some variations of the formulae(C1)-(C5), R⁶ is methyl. In some variations of the formulae (C1)-(C5),R⁵ is H. In some variations of the formulae (C1)-(C5), R⁵ is methyl. Insome variations of the formula (Cl), R^(8c) is H, OH or methyl. In somevariations of the formula (C1), R^(8c) is H or OH. In some variations ofthe formula (C1), R^(8c) is H. In some variations of the formula (C1),R^(8c) is OH. In some variations of the formula (C1), R^(8c) is OH andR^(8d) is H or methyl. In some variations of the formula (C1) or (C2),R^(8d) is H or methyl. In some variations of the formula (C1) or (C2),R^(8d) is H. In some variations of the formula (C1) or (C2), R^(8d) isunsubstituted C₁-C₈ alkyl (e.g., methyl). In some variations of theformula (C2), R^(8d) is H or methyl, and the

bond indicates the presence of an E double bond configuration. In somevariations of the formula (C2), R^(8d) is H or methyl, and the

bond indicates the presence of a Z double bond configuration. In somevariations of the formula (C4), Y is NR¹¹ where R¹¹ is H or methyl. Insome variations of the formula (C4), Y is NR¹¹ where R¹¹ is H. In somevariations of the formula (C4), Y is NR¹¹ where R¹¹ is unsubstitutedC₁-C₈ alkyl (e.g., methyl). In some variations of the formula (C4), Y isO. In some variations of the formula (C4), each R^(12a) and R^(12b) is Hor unsubstituted C₁-C₈ alkyl (e.g., methyl). In some variations of theformula (C4), each R^(12a) and R^(12b) is H. In some variations of theformula (C4), one of R^(12a) and R^(12b) is H and the other is methyl.In some variations of the formula (C4), Y is NR¹¹ where R¹¹ is H ormethyl, and each R^(12a) and R^(12b) is H.

In some variations of the formulae (C1)-(C5), D is a substituted orunsubstituted aryl. In some embodiments, the substituted aryl is otherthan substituted phenyl. In some embodiments, the unsubstituted aryl isother than unsubstituted phenyl. Examples of aryl include, but are notlimited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl,phenanthracenyl, and the like. Examples of substituted aryl include, butare not limited to, fluorophenyl (e.g. 4-fluorophenyl),aminosulfonylphenyl, (e.g., 2-(aminosulfonyl)phenyl,3-(aminosulfonyl)phenyl and 4-(aminosulfonyl)phenyl),methanesulfonylphenyl (e.g., 4-(methanesulfonyl)phenyl), pyridylphenyl(e.g., 4-(pyridine-4-yl)phenyl), and the like.

In some variations of the formulae (C1)-(C5), D is a substituted orunsubstituted heteroaryl. Examples of unsubstituted heteroaryl include,but are not limited to, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl andpyridine-4-yl), pyrimidyl (e.g., 5-pyrimidyl, 2-pyrimidyl, and4-pyrimidyl), furanyl (e.g., furan-2-yl and furan-3-yl), thiophenyl(e.g., 2-thiophenyl and 3-thiophenyl), thiazolyl (e.g., 5-thiazolyl),pyrrolyl (e.g., pyrrol-2-yl and pyrrol-3-yl), and the like. Examples ofsubstituted heteroaryl include, but are not limited to, methylpyridyl(e.g. 6-methylpyridin-3-yl, 2-methylpyridin-4-yl, 3-methylpyridin-4-yl),N-oxo-pyridyl, 2-methyl-1-oxo-pyridin-4-yl, 6-methyl-1-oxo-pyridin-3-yl,2,6-dimethylpyridin-4-yl, pyridylpyridyl (e.g.,5-(pyridine-4-yl)pyridine-2-yl), 1-methylpyrrol-3-yl,2-methlyfuran-3-yl, methylthiophenyl (e.g., 5-methylthiophen-2-yl,3-methylthiophen-2-yl), pyridylthiophenyl (e.g.,4-(pyridine-4-yl)thiophen-3-yl), aminosulfonylthiophenyl,2-aceylamido-5-thiazolyl, and the like.

In some variations of the formulae (C1)-(C5), D is selected from thegroup consisting of 4-fluorophenyl, pyridin-4-yl, pyridine-3-yl,6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and4-phenylthiazol-2-yl. In some variations of the formulae (C1)-(C4), D isselected from the group consisting of phenyl, 4-fluorophenyl,pyridin-4-yl, pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl,thiazol-2-yl, and 4-phenylthiazol-2-yl.

In some embodiments, in compounds of the formulae (C1)-(C5), D is agroup having the formula -Q^(A)-Q^(B), wherein Q^(A) is substituted arylor substituted heteroaryl and Q^(B) is substituted or unsubstituted arylor substituted or unsubstituted heteroaryl. In some embodiments, Q^(A)is aryl (e.g., phenyl). In some embodiments, Q^(A) is a 6-memberedheteroaryl containing one annular heteroatom (e.g., pyridyl). In someembodiments, Q^(A) is a 6-membered heteroaryl containing more than oneannular heteroatoms, such as a 6-membered heteroaryl containing twoannular heteroatoms (e.g., pyrimidyl and pyrazinyl). In someembodiments, Q^(A) is a 5-membered heteroaryl containing one annularheteroatom (e.g., thiophenyl, furanyl and pyrrolyl). In someembodiments, Q^(A) is a 5-membered heteroaryl containing more than oneannular heteroatoms such as a 5-membered heteroaryl containing twoannular heteroatoms (e.g., thiazolyl, oxazolyl, imidazolyl, isothiazoyl,isooxazolyl and pyrazolyl). In some embodiments, Q^(B) is a substitutedor unsubstituted aryl (e.g., phenyl, fluorophenyl and chlorophenyl). Insome embodiments, Q^(B) is a substituted or unsubstituted heteroarylsuch as a substituted or unsubstituted pyridyl, pyrimidyl, pyrazinyl,thiophenyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, imidazolyl,isothiazoyl, isooxazolyl, pyrazolyl, naphthyl, quinolinyl,isoquinolinyl, indolyl, benzofuranyl, benzothiopheyl, and the like. Insome embodiments, the Q^(A) moiety may be attached to the parentstructure at any viable annular atom of Q^(A). In some embodiments, thebond between Q^(A) and Q^(B) is between any viable annular atom of Q^(A)and any viable annular atom of Q^(B).

Examples of D moieties having the formula -Q^(A)-Q^(B), e.g., whereQ^(A) is a substituted aryl or 5- or 6-membered heteroaryl containingone annular heteroatom, that are contemplated for the formulae(C1)-(C5), include but are not limited to the following:

All variations referring to formula (IA), such as formulae (C1)-(C5),where applicable, may apply to formula (IB), the same as if each andevery variation were specifically and individually listed.

The invention also embraces compounds of formulae (J-1) to (J-5):

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety ora cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h),where present, is independently H, hydroxyl, alkoxy, acyloxy, thiol,—S-alkyl, —S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl,—SO₂-alkyl, —SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino,halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈alkenyl, C₁-C₈ perhaloalkyl, carboxyl, carbonylalkoxy, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkylsubstituted with a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations of formulae (J-1)-(J-5), at least one of X¹, X² andX³ is CH or CR⁶. In another variation, at least one of X¹, X² and X³ isN. In another variation, one of X¹, X² and X³ is N. In one variation, X¹is N and each X² and X³ is independently CH or CR⁶. In anothervariation, X² is N and each X¹ and X³ is independently CH or CR⁶. In yetanother variation, X³ is N and each X¹ and X² is independently CH orCR⁶. In another variation, two of X¹, X² and X³ is N. In one variation,each X¹ and X³ is N and X² is CH or CR⁶.

In a particular embodiment, compounds of formulae (J-1)-(J-5) areprovided wherein the ring comprising X¹, X² and X³ is a phenyl, pyridyl,pyrimidinyl or pyrazinyl ring, optionally substituted with 0-2 R⁶ groups(i.e., (R⁶)_(n) where n is 0, 1 or 2). In some such embodiments, n is 1or 2 and each R⁶ is independently halo, methyl or CF₃.

In particular variation, compounds of formulae (J-1)-(J-5) have thestructure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, and Qare defined as for formulae (J-1) to (J-5) and, where applicable, anyvariation thereof detailed herein. That is, variations of formulae(J-1)-(J-5) detailed throughout, where applicable, apply to formulae(J-1a)-(J-5a) the same as if each and every variation were specificallyand individually listed for formulae (J-1a)-(J-5a). Pharmaceuticallyacceptable salts of compounds of formulae (J-1a)-(J-5a) are alsoprovided.

In particular variation, compounds of formula (J-1a) have the structure:

or a salt or solvate thereof; wherein R¹, R⁵, X¹, X² and X³ are definedas for formula (J-1a) and, where applicable, any variation thereofdetailed herein, i is 0-5, j is 0-4, k is 0-3, Z is NH, N—CH₃, O or S,and each W is independently hydroxyl, halo, nitro, cyano, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₁-C₈ alkoxy,C₁-C₈ perhaloalkyl, C₁-C₈ perhaloalkoxy, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted aryloxy, substitutedor unsubstituted heteroaryl, substituted or unsubstituted cycloalkyl,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaralkyl, substituted or unsubstituted amino, aminoacyl, acyl, acylamino,acyloxy, carbonylalkoxy, carboxyl, thiol, thioalkyl, aminocarbonylamino,aminocarbonylalkoxy, aminosulfonyl, or sulfonylamino. In one particularaspect of this variation, W is substituted or unsubstituted aryl, orsubstituted or unsubstituted heteroaryl. In one particular aspect ofthis variation, Z is S. In another particular aspect of this variation,one of X¹, X² or X³ is N. Variations of formula (J-1a) detailedthroughout, where applicable, apply equally to any of formulae(J-1b)-(J-1d), the same as if each and every variation were specificallyand individually listed for formula (J-1b)-(J-1d). Pharmaceuticallyacceptable salts of compounds of formulae (J-1b)-(J-1d) are alsoprovided.

In some variations of formulae (J-1b)-(J-1d), at least one of X¹, X² andX³ is CH or CR⁶. In another variation, at least one of X¹, X² and X³ isN. In another variation, one of X¹, X² and X³ is N. In one variation, X¹is N and each X² and X³ is independently CH or CR⁶. In anothervariation, X² is N and each X¹ and X³ is independently CH or CR⁶. In yetanother variation, X³ is N and each X¹ and X² is independently CH orCR⁶. In another variation, two of X¹, X² and X³ is N. In one variation,each X¹ and X³ is N and X² is CH or CR⁶.

The invention also embraces compounds of formulae (K-1) to (K-5):

or a salt or solvate thereof, wherein:

R¹ is H, hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substitutedor unsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈alkynyl, perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy;

each R^(2a), R^(2b) R^(3a), R^(3b), R^(4a), R^(4b), R^(10a) and R^(10b)is independently H, hydroxyl, nitro, cyano, halo, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, carboxyl, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, alkylsulfonylamino, orcarbonylalkylenealkoxy, or is taken together with the carbon to which itis attached and a geminal R², R³, R⁴ or R¹⁰ to form a carbonyl moiety ora cycloalkyl moiety;

R⁵ is H or unsubstituted C₁-C₈ alkyl;

each X¹, X² and X³ is independently N, CH or CR⁶;

each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl;

each R^(8a), R^(8b), R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h)is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety,

-   -   or is taken together with a geminal R^(8(a-h)) to form a        substituted or unsubstituted methylene moiety or a moiety of the        formula —OCH₂CH₂O—, or is taken together with a geminal        R^(8(a-h)) and the carbon to which they are attached to form a        carbonyl moiety or a cycloalkyl moiety,    -   or is taken together with a vicinal R^(8(a-h)) and the carbon        atoms to which they are attached to form a substituted or        unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted        C₃-C₈ cycloalkenyl, or substituted or unsubstituted heterocyclyl        moiety,    -   or is taken together with a vicinal R^(8(a-h)) to form a bond        provided when an R^(8(a-h)) is taken together with a vicinal        R^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other than        hydroxyl and thiol; and

Q is substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₃-C₈ cycloalkenyl, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted amino, alkoxy, aminoacyl,acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹is H or a substituted or unsubstituted C₁-C₈ alkyl and R^(10a) andR^(10b) are taken together with the carbon to which they are attached toform a substituted or unsubstituted cycloalkyl, cycloalkenyl orheterocyclyl moiety.

In some variations of formulae (K-1)-(K-5), at least one of X¹, X² andX³ is CH or CR⁶. In another variation, at least one of X¹, X² and X³ isN. In another variation, one of X′, X² and X³ is N. In one variation, X¹is N and each X² and X³ is independently CH or CR⁶. In anothervariation, X² is N and each X¹ and X³ is independently CH or CR⁶. In yetanother variation, X³ is N and each X¹ and X² is independently CH orCR⁶. In another variation, two of X¹, X² and X³ is N. In one variation,each X¹ and X³ is N and X² is CH or CR⁶.

In a particular embodiment, compounds of formulae (K-1)-(K-5) areprovided wherein the ring comprising X¹, X² and X³ is a phenyl, pyridyl,pyrimidinyl or pyrazinyl ring, optionally substituted with 0-2 R⁶ groups(i.e., (R⁶)_(n) where n is 0, 1 or 2). In some such embodiments, n is 1or 2 and each R⁶ is independently halo, methyl or CF₃.

In particular variation, compounds of formulae (K-1)-(K-5) have thestructure:

or a salt or solvate thereof; wherein R¹, R⁵, R⁶, R^(8a), R^(8b),R^(8c), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), where present, and Qare defined as for formulae (K-1)-(K-5) and, where applicable, anyvariation thereof detailed herein. That is, variations of formulae(K-1)-(K-5) detailed throughout, where applicable, apply to formulae(K-1a)-(K-5a) the same as if each and every variation were specificallyand individually listed for formulae (K-1a)-(K-5a). Pharmaceuticallyacceptable salts of compounds of formulae (K-1a)-(K-5a) are alsoprovided.

In certain embodiments, compounds are provided wherein R¹ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, thiol, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy. In specific embodiments, R¹ is asubstituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy,substituted or unsubstituted heterocyclyl or substituted orunsubstituted aryl. In more specific embodiments, R¹ is an unsubstitutedC₁-C₈ alkyl such as methyl and cyclopropyl.

In certain embodiments, compounds are provided wherein R¹ is H,hydroxyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, substituted orunsubstituted amino, acylamino, aminoacyl, aminocarbonylamino,aminocarbonyloxy, aminosulfonyl, sulfonylamino, sulfonyl orcarbonylalkylenealkoxy. In more specific embodiments, R¹ is a sulfonylsuch as —SO₂-alkyl, —SO₂-aryl and —SO₂-aralkyl.

In certain embodiments, compounds are provided where R¹ is selected fromthe following moieties:

In certain embodiments, compounds are provided where each R^(2a) andR^(2b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro or R^(2a) and R^(2b) are takentogether to form a carbonyl moiety. In specific embodiments, each R^(2a)and R^(2b) is independently H, methyl, fluoro or R^(2a) and R^(2b) aretaken together to form a carbonyl moiety. In a specific embodiment,R^(2a) and R^(2b) are both H.

In certain embodiments, compounds are provided where each R^(3a) andR^(3b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro or R^(3a) and R^(3b) are takentogether to form a carbonyl moiety. In specific embodiments, each R^(3a)and R^(3b) is independently H or fluoro. In another specific embodiment,R^(3a) and R^(3b) are both H. In a further specific embodiment, R^(3a)and R^(3b) are both H and R^(2a) and R^(2b) are both H.

In certain embodiments, compounds are provided where each R^(4a) andR^(4b) is independently H, substituted or unsubstituted C₁-C₈ alkyl,halo, cyano, hydroxyl, alkoxy, nitro or R^(4a) and R^(4b) are takentogether to form a carbonyl moiety. In specific embodiments, each R^(4a)and R^(4b) is independently H, halo, hydroxyl or methyl or R^(4a) andR^(4b) are taken together to form a carbonyl moiety. In another specificembodiment, R^(4a) and R^(4b) are both H. In a further specificembodiment, R^(4a) and R^(4b) are both H and R^(2a), R^(2b), R^(3a) andR^(ab) are each H.

In certain embodiments, compounds are provided where each X¹, X² and X³is independently N, CH or CR⁶. In certain embodiments, each X¹, X² andX³ is CH or CR⁶, such that the ring comprising X¹, X² and X³ is anoptionally substituted phenyl ring. In specific embodiments, X² is CR⁶where R⁶ is halo or alkyl and X¹ and X³ are each CH. In otherembodiments, one of X¹, X² and X³ is N, and the others are CH or CR⁶,such that the ring comprising X¹, X² and X³ is an optionally substitutedpyridine ring. In further embodiments, two of X¹, X² and X³ are N, andthe other is CH or CR⁶, such that the ring comprising X¹, X² and X³ isan optionally substituted pyrimidine or pyrazine ring.

In certain embodiments, compounds are provided where each R⁶, wherepresent, is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl, carbonylalkylenealkoxy,alkylsulfonylamino or acyl. In one variation, at least one of X¹-X³ isCR⁶ where R⁶ is halo. In a particular variation, one of X¹-X³ is CR⁶where R⁶ is chloro and the others are CH. In a specific variation, X¹and X³ are each CH and X² is CR⁶ where R⁶ is chloro.

In certain embodiments, compounds are provided where each R⁶, wherepresent, is independently hydroxyl, halo, C₁-C₈ perhaloalkyl,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, C₁-C₈perhaloalkoxy, C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl,substituted or unsubstituted aralkyl, thioalkyl, substituted orunsubstituted amino, alkylsulfonylamino or acyl. In further embodiments,each R⁶, where present, is independently hydroxyl, halo, C₁-C₄perhaloalkyl, substituted or unsubstituted C₁-C₄ alkyl, substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, or C₁-C₄alkoxy; or in still a further variation, each R⁶, where present, isindependently halo, unsubstituted C₁-C₄ alkyl or C₁-C₄ perhaloalkyl.

In specific embodiments, the ring comprising X¹, X² and X³ is a phenyl,pyridyl, pyrimidinyl or pyrazinyl ring, optionally substituted with 0-2R⁶ groups (i.e., (R⁶)_(n)) where n is 0, 1 or 2. In some suchembodiments, n is 1 or 2 and each R⁶ is independently halo, methyl orCF₃.

In certain embodiments, compounds are provided where Q is a substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted cycloalkyl, substituted or unsubstitutedcycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy,aminocarbonylalkoxy or acylamino. In one variation, compounds are of theformula (IA) or (IB) where Q is a substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl orsubstituted or a unsubstituted heterocyclyl. In certain embodiments, Qis a substituted or unsubstituted 5- or 6-membered aryl or heteroaryl.In some such embodiments, Q is a substituted or unsubstituted phenyl,pyridyl or pyrimidinyl ring. When Q is substituted, it is frequentlysubstituted with from 1-3 substituents selected from group consisting ofhalo, C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, and C₁-C₄ alkoxy.

In a particular variation, Q is a substituted heteroaryl, amono-substituted aryl group substituted with a chloro or alkyl group ora di- or tri-substituted aryl moiety. For instance,

each Q in one variation is independently selected from the groupconsisting of 4-methoxy-3-fluorophenyl, 3,4-di-fluorophenyl,4-chloro-3-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluorophenyl,2,4-difluorophenyl, 2,4-dichlorophenyl, 2,4,6-trifluorophenyl,4-chlorophenyl, 4-methylphenyl, 6-methyl-3-pyridyl,6-trifluoromethyl-3-pyridyl, 5-trifluoromethyl-3-pyridyl andpyrimidinyl. In one aspect, Q is a substituted pyridyl such as6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl and5-trifluoromethyl-3-pyridyl.

In certain embodiments, R¹ is a substituted or unsubstituted C₁-C₈alkyl, acyl, acyloxy, carbonylalkoxy, substituted or unsubstitutedheterocyclyl or substituted or unsubstituted aryl; each R^(2a) andR^(2b) is independently H, methyl, fluoro or R^(2a) and R^(2b) are takentogether to form a carbonyl moiety; each R^(3a) and R^(3b) isindependently H or fluoro; and each R^(4a) and R^(4b) is independentlyH, halo, hydroxyl or methyl or R^(4a) and R^(4b) are taken together toform a carbonyl moiety. In particular variations, R¹ is an unsubstitutedC₁-C₈ alkyl and R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) areeach H. In still a further variation, R¹ is an unsubstituted C₁-C₈alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are each H andQ is selected from the group consisting of 4-methoxy-3-fluorophenyl,3,4-di-fluorophenyl, 4-chloro-3-fluorophenyl, 3,4-dichlorophenyl,3-chloro-4-fluorophenyl, 2,4-difluorophenyl, 2,4-dichlorophenyl,2,4,6-trifluorophenyl, 4-chlorophenyl, 4-methylphenyl,6-methyl-3-pyridyl, 6-trifluoromethyl-3-pyridyl,5-trifluoromethyl-3-pyridyl and pyrimidinyl. In still a furthervariation of formula (IA) or (IB), R¹ is an unsubstituted C₁-C₈ alkyl,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), and R^(4b) are each H and X² isCR⁶ where R⁶ is chloro. In yet a further variation, R¹ is anunsubstituted C₁-C₈ alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) andR^(4b) are each H, X² is CR⁶ where R⁶ is chloro and Q is a substitutedor unsubstituted aryl or a substituted or substituted heteroaryl. In onesuch variation, Q is a substituted phenyl.

In particular embodiments, each X¹, X² and X³ is CH or CR⁶. In otherembodiments, compounds are provided where at least one of X¹, X² and X³is N. Another variation provides a compound where at least two of X¹, X²and X³ are N. A further variation provides a compound where two of X¹,X² and X³ are N and one of X¹, X² and X³ is CH or CR⁶. Compounds whereone of X¹, X² and X³ is N and two of X¹, X² and X³ are CH or CR⁶ arealso embraced by this invention.

In another variation, compounds are provided wherein the ring comprisingX¹, X² and X³ is an aromatic moiety selected from the followingstructures:

where each R⁶ is as defined. In a particular variation, each R⁶ isindependently hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy,C₁-C₈ alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl. In a further variation, each R⁶ isindependently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl, orC₁-C₄ alkoxy.

In still a further variation, compounds are provided wherein the ringcomprising X¹, X² and X³ is an aromatic moiety selected from thefollowing structures:

wherein R⁶ is as defined herein; or in a particular variation, where R⁶is hydroxyl, halo, C₁-C₈ perhaloalkyl, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, C₁-C₈alkoxy, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, substituted or amino,alkylsulfonylamino or acyl; or in still a further variation, where eachR⁶ is independently halo, unsubstituted C₁-C₄ alkyl, C₁-C₄ perhaloalkyl,or C₁-C₄ alkoxy.

In a further variation, compounds are provided wherein the ringcomprising X¹, X² and X³ is an aromatic moiety selected from thefollowing structures:

Any formula detailed herein, where applicable, may in one variation haveX¹, X² and X³ taken together to provide an aromatic moiety detailedherein above. It is understood that by “where applicable” it is intendedthat in one variation such X¹, X² and X³ groups are taken together toprovide a moiety hereinabove if the formula encompasses such astructure. For example, if a given formula does not encompass structureswherein X¹, X² and X³ groups are taken together provide a pyridylmoiety, then a pyridyl moiety as detailed hereinabove is not applicableto that particular formula, but remains applicable to formulae that doencompass structures where X¹, X² and X³ groups are taken togetherprovide a pyridyl moiety.

In another embodiment, compounds are provided wherein X¹-X³ are asdefined herein or as detailed in any variation herein, where R¹ is H,substituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, substituted orunsubstituted aralkyl. In a further embodiment, compounds are providedwherein X¹-X³ are as defined herein or as detailed in any variationherein, where R¹ is a substituted or unsubstituted C₁-C₈ alkyl, acyl,acyloxy, carbonylalkoxy, substituted or unsubstituted heterocyclyl orsubstituted or unsubstituted aryl. In a particular variation, compoundsare provided wherein X¹-X³ are as defined herein or as detailed in anyvariation herein, where R¹ is methyl, ethyl, cyclopropyl, propylate,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In another variation, the compound of the invention is provided whereX¹-X³ and R¹ are as defined herein or as detailed in any variationherein, where R^(2a) and R^(2b) are independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or R^(2a) and R^(3b) aretaken together to form a carbonyl moiety and each R^(3a) and R^(3b) isindependently H, substituted or unsubstituted C₁-C₈ alkyl, halo, cyanoor nitro. In another variation, the compound of the invention isprovided where X¹-X³ and R¹ are as defined herein or as detailed in anyvariation herein, where each R^(2a) and R^(2b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b) are taken togetherto form a carbonyl moiety and each R^(3a) and R^(3b) is independently H,unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b) are taken togetherto form a carbonyl moiety. In still a further variation, the compound ofthe invention is provided where X¹-X³ and R¹ are as defined herein or asdetailed in any variation herein, where each R^(2a) and R^(2b) isindependently H, unsubstituted C₁-C₈ alkyl, halo or R^(2a) and R^(2b)are taken together to form a carbonyl moiety; and each R^(3a) and R^(3b)is independently H, unsubstituted C₁-C₈ alkyl, halo or R^(3a) and R^(3b)are taken together to form a carbonyl moiety. The invention alsoembraces compounds of the invention where X¹-X³ and R¹ are as definedherein or as detailed in any variation herein, where each R^(2a) andR^(2b) is independently H, methyl, halo or R^(2a) and R^(2b) are takentogether to form a carbonyl moiety and each R^(3a) and R^(3b) isindependently H, methyl, halo or R^(3a) and R^(3b) are taken together toform a carbonyl moiety.

The invention further embraces compounds of the invention where X¹-X³and R¹ are as defined herein or as detailed in any variation herein,where each R^(2a), R^(2b), R^(4a) and R^(4b) is H. In one variation,compounds are provided where X¹-X³ and R¹ are as defined herein or asdetailed in any variation herein, where at least one of R^(2a), R^(2b),R^(4a) and R^(4b) is a substituted or unsubstituted C₁-C₈ alkyl, halo,cyano, nitro or is taken together with a geminal R² or R⁴ to form acarbonyl moiety.

In another variation, compounds are provided where X¹-X³ and R¹ are asdefined herein or as detailed in any variation herein, where at leasttwo of R^(2a), R^(2b), R^(4a) and R^(4b) is a substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro or is taken together witha geminal R² or R⁴ to form a carbonyl moiety. In yet another variation,compounds are provided where X¹-X³ and R¹ are as defined herein or asdetailed in any variation herein, where at least one of R^(2a), R^(2b),R^(4a) and R^(4b) is fluoro or methyl or is taken together with ageminal R² or R⁴ to form a carbonyl moiety.

When any carbon of the preceding formulae bearing R², R^(2a) and R^(2b),or R^(3a) and R^(3b), R⁴, or R^(4a) and R^(4b), where present, isoptically active, it may be in the (R)— or (S)-configuration andcompositions comprising substantially pure (R) or (S) compound ormixtures thereof in any amount are embraced by this invention.

In one variation, compounds are provided wherein the ring comprising N,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selectedfrom the following structures:

wherein R¹, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) are asdefined, and p is 1 or 2.

In another variation, compounds are provided wherein the ring comprisingN, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moietyselected from the following structures:

wherein R¹, R^(2b), R^(3a), R^(3b), R^(4a), and R^(4b) are as defined,and p is 1 or 2.

In another variation, compounds are provided wherein the ring comprisingN, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moietyselected from the following structures:

In another variation, compounds are provided wherein the ring comprisingN, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety tyselected from the following structures:

In any one of the variations of compounds of the formulae describedherein, all stereoisomers are intended. For example, the ring can beeither

Where more than one stereocenter is present, it is understood that allsuch stereoisomers are intended. For example, a compound having twostereocenters may be present in the (S),(S); (S),(R); (R),(R); and(R),(S) forms. Compositions comprising a single stereoisomer or mixturesof more than one stereoisomer are also intended. Compositions comprisinga mixture of stereoisomers in any ratio are embraced, including mixturesof two or more stereochemical forms of a compound of the invention inany ratio, such that racemic, non-racemic, enantioenriched and scalemicmixtures of a compound are embraced.

In some embodiments, the ring comprising N, R^(2a), R^(2b), R^(3a),R^(3b), R^(4a), and R^(4b) is a moiety selected from the followingstructures:

where R¹ in the structures above is as defined or as in any particularvariation detailed herein. In some embodiments, the ring comprising N,R^(2a), R^(2b), R^(3a), R^(3b), R^(4a) and R^(4b) is a moiety selectedfrom the following structures:

where R¹ is as defined or as in any particular variation detailedherein. Any formula detailed herein, where applicable, may in onevariation have a ring according to the structures above.

Compounds according to any formulae detailed herein, or any variation ofthe foregoing, where applicable, in one variation is provided where m,n, o, p, and R^(8(a-h)), if present and where applicable, are takentogether to form a moiety selected from the group consisting of thestructures:

When the above structures are applied to the formulae herein, or anyvariation thereof, it is understood that m, n, o, p and R^(8(a-h)),where applicable, are taken together to form the foregoing moieties,including but not limited to, the structures of this paragraph.Likewise, any formula detailed herein, where applicable, may in onevariation have m, n, o, p and R^(8(a-h)), if present, taken together toform a moiety as detailed herein above, including but not limited to,the structures of this paragraph. It is understood that by “whereapplicable” it is intended that in one variation such m, n, o, p andR^(8(a-h)) groups, if present, are taken together to provide a moietyhereinabove if the formula encompasses such a structure. For example, ifa given formula does not encompass structures wherein m, n, o, p andR^(8(a-h)) groups, if present, are taken together to provide a —CH₂CH₂—moiety, then a —CH₂CH₂— moiety as detailed hereinabove is not applicableto that particular formula, but remains applicable to formulae that doencompass structures where m, n, o, p and R^(8(a-h)) groups, if present,are taken together to provide a —CH₂CH₂— moiety.

In one aspect, at least one of R^(8(a-h)) is a C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety.

Compounds according to any formulae detailed herein, or any variation ofthe foregoing, where applicable, in one variation are provided where oneor more of R^(8(a-h)) and the carbon to which it is attached, togetherwith a vicinal R⁸ and the carbon to which it is attached, form a moietyselected from the group consisting of the structures, each of which maybe optionally substituted, where each R⁸ is independently H, hydroxyl,C₁-C₈ alkyl, C₁-C₈ perhaloalkyl, carboxy or carbonylalkoxy:

In another variation, any double bond, if present in the cycloalkenylring, may also be present at any location in the ring, where chemicallyfeasible, as exemplified above for the cyclopropenyl moiety.

In certain embodiments, compounds are provided where Q is a substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl, whichmay be but is not limited to a substituted or unsubstituted pyridyl,phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl orthiophenyl group. In one variation, Q is a substituted or unsubstitutedphenyl or pyridyl group. In a particular variation, Q is a phenyl orpyridyl group substituted with at least one methyl, trifluoromethyl,methoxy or halo substituent. In another variation, Q is a pyridyl,phenyl, pyrimidinyl, pyrazinyl, imidazolyl, furanyl, pyrrolyl orthiophenyl group substituted with at least one substituted orunsubstituted C₁-C₄ alkyl, C₁-C₄ alkoxy, halo or C₁-C₄ perhaloalkylmoiety.

In still another variation, a compound of the invention is providedwhere Q is a substituted or unsubstituted C₃-C₈ cycloalkyl or asubstituted or unsubstituted heterocyclyl. In another variation, Q is asubstituted or unsubstituted C₃-C₈ cycloalkyl or a substituted orunsubstituted heterocyclyl. In yet another variation, a compound of theinvention is provided where Q is a substituted or unsubstituted pyridyl,phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinyl group.In a particular variation, Q is a pyridyl, phenyl, pyrazinyl,piperazinyl, pyrrolidinyl or thiomorpholinyl group substituted with atleast one methyl, CF₃, methoxy or halo group.

In one variation, a compound of the invention is provided where Q is anunsubstituted cycloalkyl or an unsubstituted heterocyclyl. In anothervariation, Q is an unsubstituted C₃-C₈ cycloalkyl or an unsubstitutedheterocyclyl. In another variation, a compound of the invention isprovided where Q is a substituted or unsubstituted cyclohexyl,morpholinyl, piperazinyl, thiomorpholinyl, cyclopentyl or pyrrolidinylmoiety. In yet another variation, a compound of the invention isprovided where Q is a substituted cyclohexyl, morpholinyl, piperazinyl,thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety substituted with atleast one carbonyl, hydroxymethyl, methyl or hydroxyl group. Q groupsmay be attached to the parent structure at any available position on theQ moiety. Thus, although specific attachment points for certain Qmoieties are depicted herein, it is understood that such Q moieties, mayalso be connected to the parent structure at any available position. Forexample, if a mono-fluoro-phenyl is depicted herein, it is understoodthat each of the available mono-fluoro-phenyl moieties are intended,e.g., 2-fluoro-phenyl, 3-fluoro-phenyl and 4-fluoro-phenyl. It is alsounderstood that any formula detailed herein, where applicable, may inone variation have a Q moiety as detailed herein and below.

In still another variation, compounds are provided where Q is a moietyselected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl(C₁-C₈), perhaloalkoxy (C₁-C₈), substituted or unsubstituted C₁-C₈alkyl, substituted or unsubstituted C₂-C₈ alkenyl, substituted orunsubstituted C₂-C₈ alkynyl, acyl, acyloxy, carbonylalkoxy, thioalkyl,substituted or unsubstituted heterocyclyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In one variation, Q is substituted with two R⁹groups. In a further variation, Q is selected from the aromaticstructures detailed where the residue has the moiety (R⁹)₀ such that Qeither contains no R⁹ functionality or a moiety of the formula N—R⁹.

In one variation, Q is substituted with no more than one R⁹ group. Inanother variation, Q is substituted with only one R⁹ group. In onevariation, Q is substituted with two R⁹ groups. In a further variation,Q is selected from the aromatic structures detailed where the residuehas the moiety (R⁹)₀ such that each Q either contains no R⁹functionality or a moiety of the formula N—R⁹.

In another variation, compounds are provided where Q is a moietyselected from the structures:

and wherein R⁹ is connected to any annular carbon atom. In a particularvariation, Q is a structure of the formula:

and R⁹ is connected to Q ortho or para to the position at which Q isconnected to the parent structure. In another particular variation, Q isa structure of the formula

where each R⁹ is independently alkyl, perhaloalkyl or halo.

In another variation, compounds are provided where Q is a moietyselected from the structures:

wherein each R⁹ is independently a halo, cyano, nitro, perhaloalkyl,perhaloalkoxy, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,acyl, acyloxy, carbonylalkoxy, thioalkyl, alkoxy, substituted orunsubstituted amino, acylamino, sulfonylamino, sulfonyl, carbonyl,aminoacyl or aminocarbonylamino. In one variation, Q is substituted withno more than one R⁹ group. In another variation, Q is substituted withonly one R⁹ group. In yet another variation, Q is substituted with twoR⁹ groups. In a particular variation, Q is selected from the carbocyclicand heterocyclic structures detailed where the residue has the moiety(R⁹)₀ such that each Q either contains no R⁹ functionality or a moietyof the formula N—R⁹.

In any structure or variation detailed herein containing an R⁹ group, inone variation, each R⁹ is independently a substituted or unsubstitutedC₁-C₄ alkyl, halo, trifluoromethyl or hydroxyl. In another variation,each R⁹ is independently methyl, —CH₂OH, isopropyl, halo,trifluoromethyl or hydroxyl.

In another variation, compounds are provided where Q is an aromaticmoiety selected from the structures:

In another variation, compounds are provided where Q is a heteroaromaticmoiety selected from the structures:

In some embodiments, in compounds of the formulae (IA), (IB),(IA1)-(IA3), (A1)-(A5), (B1)-(B10), (J-1)-(J-5), and (K-1)-(K-5) and anyvariations detailed herein, where applicable, Q is a substituted orunsubstituted aryl. In some embodiments, the substituted aryl is otherthan substituted phenyl. In some embodiments, the unsubstituted aryl isother than unsubstituted phenyl. Examples of aryl include, but are notlimited to, phenyl, 1-naphthyl, 2-naphthyl, anthracenyl,phenanthracenyl, and the like. Examples of substituted aryl include, butare not limited to, fluorophenyl (e.g. 4-fluorophenyl),aminosulfonylphenyl, (e.g., 2-(aminosulfonyl)phenyl,3-(aminosulfonyl)phenyl and 4-(aminosulfonyl)phenyl),methanesulfonylphenyl (e.g., 4-(methanesulfonyl)phenyl), pyridylphenyl(e.g., 4-(pyridine-4-yl)phenyl), and the like.

In some embodiments, in compounds of the formulae (IA), (IB),(IA1)-(IA3), (A1)-(A5), (B1)-(B10), (J-1)-(J-5), and (K-1)-(K-5) and anyvariations detailed herein, where applicable, Q is a substituted orunsubstituted heteroaryl. Examples of unsubstituted heteroaryl include,but are not limited to, pyridyl (e.g., pyridin-2-yl, pyridin-3-yl andpyridine-4-yl), pyrimidyl (e.g., 5-pyrimidyl, 2-pyrimidyl, and4-pyrimidyl), furanyl (e.g., furan-2-yl and furan-3-yl), thiophenyl(e.g., 2-thiophenyl and 3-thiophenyl), thiazolyl (e.g., 5-thiazolyl),pyrrolyl (e.g., pyrrol-2-yl and pyrrol-3-yl), and the like. Examples ofsubstituted heteroaryl include, but are not limited to, methylpyridyl(e.g. 6-methylpyridin-3-yl, 2-methylpyridin-4-yl, 3-methylpyridin-4-yl),N-oxo-pyridyl, 2-methyl-1-oxo-pyridin-4-yl, 6-methyl-1-oxo-pyridin-3-yl,2,6-dimethylpyridin-4-yl, pyridylpyridyl (e.g.,5-(pyridine-4-yl)pyridine-2-yl), 1-methylpyrrol-3-yl,2-methlyfuran-3-yl, methylthiophenyl (e.g., 5-methylthiophen-2-yl,3-methylthiophen-2-yl), pyridylthiophenyl (e.g.,4-(pyridine-4-yl)thiophen-3-yl), aminosulfonylthiophenyl,2-aceylamido-5-thiazolyl, and the like.

In some embodiments, in compounds of the formulae (IA), (IB),(IA1)-(IA3), (A1)-(A5), (B1)-(B10), (J-1)-(J-5), and (K-1)-(K-5) and anyvariations detailed herein, where applicable, Q is a group having theformula -Q^(A)-Q^(B), wherein Q^(A) is substituted aryl or substitutedheteroaryl and Q^(B) is substituted or unsubstituted aryl or substitutedor unsubstituted heteroaryl. In some embodiments, Q^(A) is aryl (e.g.,phenyl). In some embodiments, Q^(A) is a 6-membered heteroarylcontaining one annular heteroatom (e.g., pyridyl). In some embodiments,Q^(A) is a 6-membered heteroaryl containing more than one annularheteroatoms, such as a 6-membered heteroaryl containing two annularheteroatoms (e.g., pyrimidyl and pyrazinyl). In some embodiments, Q^(A)is a 5-membered heteroaryl containing one annular heteroatom (e.g.,thiophenyl, furanyl and pyrrolyl). In some embodiments, Q^(A) is a5-membered heteroaryl containing more than one annular heteroatoms suchas a 5-membered heteroaryl containing two annular heteroatoms (e.g.,thiazolyl, oxazolyl, imidazolyl, isothiazoyl, isooxazolyl andpyrazolyl). In some embodiments, Q^(B) is a substituted or unsubstitutedaryl (e.g., phenyl, fluorophenyl and chlorophenyl). In some embodiments,Q^(B) is a substituted or unsubstituted heteroaryl such as a substitutedor unsubstituted pyridyl, pyrimidyl, pyrazinyl, thiophenyl, furanyl,pyrrolyl, thiazolyl, oxazolyl, imidazolyl, isothiazoyl, isooxazolyl,pyrazolyl, naphthyl, quinolinyl, isoquinolinyl, indolyl, benzofuranyl,benzothiopheyl, and the like. In some embodiments, the Q^(A) moiety maybe attached to the parent structure at any viable annular atom of Q^(A).In some embodiments, the bond between Q^(A) and Q^(B) is between anyviable annular atom of Q^(A) and any viable annular atom of Q^(B).

Examples of Q moieties having the formula -Q^(A)-Q^(B), e.g., whereQ^(A) is a substituted aryl or 5- or 6-membered heteroaryl containingone annular heteroatom, where that are contemplated for the formulaeherein, include but are not limited to the following:

In yet another variation, compounds are provided where Q is asubstituted or unsubstituted cycloalkyl or heterocyclyl selected fromthe structures:

In any of the variations described herein for Q, only one point ofattachment of each moiety to the parent structure may be depicted,however it is understood that the moiety may be attached to the parentstructure at any position, where chemically feasible.

In another variation, compounds are provided where Q is a substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carbonylalkoxy,aminocarbonylalkoxy or acylamino moiety. In a particular variation, Q isan unsubstituted amino. In another variation, Q is a substituted aminoof the formula —N(C₁-C₈ alkyl)₂ such as the moiety —N(Me)₂ or—N(CH₃)(CH₂CH₃). In another variation, Q is a substituted amino of theformula —N(H)(cycloalkyl or substituted cycloalkyl), such as a moiety ofthe formula:

In another variation, each R² or R⁶ is independently a substituted aminoof the formula —N(H)(aryl or substituted aryl), such as a moiety of theformula:

The invention also embraces compounds where Q is an aminoacyl moiety. Inone variation, Q is an aminoacyl group where at least one of R_(a) andR_(b) is H, such as when Q is of the formula —NHC(O)R_(b). In onevariation, Q is an aminoacyl moiety selected from the group consistingof: —NHC(O)-heterocyclyl, —NHC(O)-substituted heterocyclyl,—NHC(O)-alkyl, —NHC(O)-cycloalkyl, —NHC(O)-aralkyl and—NHC(O)-substituted aryl. In another variation, Q is an aminoacyl moietyselected from the group consisting of: —NHC(O)—C₅-C₇ heterocyclyl,—NHC(O)—C₁-C₆ alkyl, —NHC(O)—C₃-C₇ cycloalkyl, —NHC(O)—C₁-C₃ aralkyl and—NHC(O)-substituted phenyl. In a particular variation, Q is a moiety ofthe formula:

In one variation, compounds are provided where Q is acyloxy.

In one variation, compounds are provided where Q is a carbonylalkoxymoiety. In one variation, Q is a carbonylalkoxy moiety of the formula—C(O)—O—R where R is H, alkyl, substituted alkyl or alkaryl. In onevariation, Q is a carbonylalkoxy moiety of the formula—C(O)—O—C₁-C₆alkyl. In a particular variation, Q is a carbonylalkoxymoiety of the formula —C(O)—O—C₂H₅. In one variation, Q is acarbonylalkoxy moiety selected from the group consisting of:—C(O)—O—C₁-C₁₀alkyl, —C(O)—O—C₁-C₃ alkaryl, —C(O)—O—C₁-C₃ substitutedalkyl and —C(O)—OH. In another variation, Q is —C(O)—O—C₁-C₆ alkyl. In aparticular variation, Q is a moiety of the formula:

In another variation, compounds are provided where Q is anaminocarbonylalkoxy moiety. In one variation, Q is anaminocarbonylalkoxy moiety of the formula —NHC(O)-β—R_(b). In anothervariation, Q is an aminocarbonylalkoxy moiety of the formula—NHC(O)—O—R_(b) where R_(b) is a substituted alkyl group. In aparticular variation, Q is a moiety of the formula —NH—C(O)—O—CH₂—CCl₃.

The invention also embraces compounds where Q is an acylamino moiety. Inone variation, Q is an acylamino group where at least one of R_(a) andR_(b) is H, such as when Q is of the formula —C(O)N(H)(R_(b)). Inanother variation, Q is an acylamino group where both R_(a) and R_(b)are alkyl. In one variation, Q is an acylamino moiety selected from thegroup consisting of: —C(O)—N(H)(alkyl), —C(O)—N(alkyl)₂,—C(O)—N(H)(aralkyl) and —C(O)—N(H)(aryl). In another variation, Q is anacylamino moiety selected from the group consisting of: —C(O)—N(H)₂,—C(O)—N(H)(C₁-C₈alkyl), —C(O)—N(C₁-C₆alkyl)₂ and —C(O)—N(H)(C₁-C₃aralkyl). In a particular variation, Q is a moiety of the formula:

In a further variation, compounds are provided where Q is a moietyselected from the structures:

In a further variation, compounds are provided where R¹ is anunsubstituted alkyl, R^(2a), R^(2b), R^(3a), R^(3b), R^(4a), and R^(4b),are each H, each X¹, X² and X³ is independently N or CH, and Q is asubstituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, including but not limited to a substituted or unsubstitutedphenyl or pyridyl group. Where Q is a substituted phenyl or pyridylgroup, in one variation it is substituted with at least one methyl orhalo group.

In yet a further variation, compounds are provided where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl, acyl, acyloxy, carbonylalkoxy,substituted or unsubstituted heterocyclyl, substituted or unsubstitutedaryl; each R^(2a) and R^(2b) is independently H, unsubstituted C₁-C₈alkyl or halo; each R^(3a) and R^(3b) is independently H or halo; eachX¹, X² and X³ is CH or CR⁶, where R⁶ is as defined or as detailed in aparticular variation, R⁶ is halo, pyridyl, methyl or trifluoromethyl;R^(4a) and R^(4b) are both H, and Q is a substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, including but not limitedto a substituted or unsubstituted pyridyl, phenyl, pyrimidinyl,pyrazinyl, imidazolyl, furanyl, pyrrolyl or thiophenyl group. In aparticular variation, Q is a pyridyl, phenyl, pyrimidinyl, pyrazinyl,imidazolyl, furanyl, pyrrolyl or thiophenyl group substituted with atleast one substituted or unsubstituted C₁-C₈ alkyl, halo or perhaloalkylmoiety. In one variation, a compound of the variation detailed herein isprovided wherein R¹ is propylate, methyl, ethyl, cyclopropyl,trifluoromethyl, isopropyl, tert-butyl, sec-butyl, 2-methylbutyl,propanal, 1-methyl-2-hydroxyethyl, 2-hydroxyethanal, 2-hydroxyethyl,2-hydroxypropyl, 2-hydroxy-2-methylpropyl, cyclobutyl, cyclopentyl,cyclohexyl, substituted phenyl, piperidin-4-yl, hydroxycyclopent-3-yl,hydroxycyclopent-2-yl, hydroxycycloprop-2-yl,1-hydroxy-1-methylcycloprop-2-yl, or1-hydroxy-1,2,2-trimethyl-cycloprop-3-yl.

In still a further variation, compounds are provided where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl; each R^(2a), R^(2b), R^(3a)and R^(3b) is independently H or halo; each R⁶ is independently halo,C₁-C₈ perhaloalkyl, substituted or a unsubstituted C₁-C₈ alkyl; and Q isa substituted or unsubstituted cyclohexyl, morpholinyl, piperazinyl,thiomorpholinyl, cyclopentyl or pyrrolidinyl moiety. The invention alsoembraces a compound of the formula (I) where R¹ is a methyl; at leastone of X¹, X² and X¹⁰ is CR⁶, and each R⁶ is independently halo, methylor trifluoromethyl. The invention embraces compounds where each Q in anyvariation detailed is independently substituted with at least onecarbonyl, hydroxymethyl, methyl or hydroxyl group, to the extent suchsubstituent makes chemical sense.

In a particular variation, a compound is provided where R¹ is asubstituted or unsubstituted C₁-C₈ alkyl; each R^(2a) and R^(2b) isindependently H, a substituted or unsubstituted C₁-C₈ alkyl or R^(2a)and R^(2b) are taken together to form a carbonyl moiety; R^(3a) andR^(3b) are both H; each R⁶ is independently halo or a substituted orunsubstituted C₁-C₈ alkyl; each R^(4a) and R^(4b) is independently H,halo, a substituted or unsubstituted C₁-C₈ alkyl, hydroxyl, alkoxy orR^(4a) and R^(4b) are taken together to form a carbonyl moiety, providedthat at least one of R^(4a) and R^(4b) is other than H. In one aspect ofthis variation, each Q may independently be a substituted orunsubstituted pyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl orthiomorpholinyl group. In another aspect of this variation, Q is apyridyl, phenyl, pyrazinyl, piperazinyl, pyrrolidinyl or thiomorpholinylgroup substituted with at least one methyl or halo group. In yet anotheraspect of this variation, X¹, X² and X³ are CH or CR⁶ and each R⁶ isindependently halo or methyl.

The embodiments and variations described herein are suitable forcompounds of any formulae detailed herein, where applicable. Forinstance, all variations referring to the formula (IA) detailed herein,such as formulae (IA1), (IA2), (IA3), (A1), (A2), (A3), (A4), (A5),(IB), (B1), (B2), (B3), (B4), (B5), (B6), (B7), (B8), (B9), B(10), (C1),(C2), (C3), (C4) and (C5), where applicable, may apply to formulae (IB),(J-1), (J-2), (J-3), (J-4), (J-5), (J-1a), (J-2a), (J-3a), (J-4-a),(J-5a), (J-1b), (J-1c), (J-1d), (K-1), (K-2), (K-3), (K-4), (K-5),(K-1a), (K-2a), (K-3a), (K-4-a) and (K-5a) the same as if each and everyvariation were specifically and individually listed. In anotherinstance, all variations referring to the formulae herein, such asformulae (IA), (IA1), (IA2) and (IA3), where applicable, may apply toformula (A1), (A2), (A3), (A4), (A5), (IB), (B1), (B2), (B3), (B4),(B5), (B6), (B7), (B8), (B9), B(10), (C1), (C2), (C3), (C4), (C5),(J-1), (J-2), (J-3), (J-4), (J-5), (J-1a), (J-2a), (J-3a), (J-4-a),(J-5a), (J-1b), (J-1c), (J-1d), (K-1), (K-2), (K-3), (K-4), (K-5),(K-1a), (K-2a), (K-3a), (K-4-a) and (K-5a) the same as if each and everyvariation were specifically and individually listed.

Representative examples of compounds detailed herein, includingintermediates and final compounds according to the invention aredepicted in the tables below. It is understood that in one aspect, anyof the compounds may be used in the methods detailed herein, including,where applicable, intermediate compounds that may be isolated andadministered to an individual.

The compounds depicted herein may be present as salts even if salts arenot depicted and it is understood that the invention embraces all saltsand solvates of the compounds depicted here, as well as the non-salt andnon-solvate form of the compound, as is well understood by the skilledartisan. In some embodiments, the salts of the compounds of theinvention are pharmaceutically acceptable salts. Where one or moretertiary amine moiety is present in the compound, the N-oxides are alsoprovided and described.

Pharmaceutical compositions of any of the compounds detailed herein areembraced by this invention. Thus, the invention includes pharmaceuticalcompositions comprising a compound of the invention or apharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier or excipient. In one aspect, the pharmaceuticallyacceptable salt is an acid addition salt, such as a salt formed with aninorganic or organic acid. Pharmaceutical compositions according to theinvention may take a form suitable for oral, buccal, parenteral, nasal,topical or rectal administration or a form suitable for administrationby inhalation.

A compound as detailed herein may in one aspect be in a purified formand compositions comprising a compound in purified forms are detailedherein. Compositions comprising a compound as detailed herein or a saltthereof are provided, such as compositions of substantially purecompounds. In some embodiments, a composition containing a compound asdetailed herein or a salt thereof is in substantially pure form. Unlessotherwise stated, “substantially pure” intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than the compound comprising the majority of thecomposition or a salt thereof. Taking compound 1 as an example, acomposition of substantially pure compound 1 intends a composition thatcontains no more than 35% impurity, wherein the impurity denotes acompound other than compound 1 or a salt thereof. In one variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains no more than 25% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 20%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 10% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 5% impurity. In anothervariation, a composition of substantially pure compound or a saltthereof is provided wherein the composition contains or no more than 3%impurity. In still another variation, a composition of substantiallypure compound or a salt thereof is provided wherein the compositioncontains or no more than 1% impurity. In a further variation, acomposition of substantially pure compound or a salt thereof is providedwherein the composition contains or no more than 0.5% impurity.

In one variation, the compounds herein are synthetic compounds preparedfor administration to an individual. In another variation, compositionsare provided containing a compound in substantially pure form. Inanother variation, the invention embraces pharmaceutical compositionscomprising a compound detailed herein and a pharmaceutically acceptablecarrier. In another variation, methods of administering a compound areprovided. The purified forms, pharmaceutical compositions and methods ofadministering the compounds are suitable for any compound or formthereof detailed herein.

Kits comprising a compound of the invention, or a salt or solvatethereof, and suitable packaging are provided. In one embodiment, a kitfurther comprises instructions for use. In one aspect, a kit comprises acompound of the invention, or a salt or solvate thereof, andinstructions for use of the compounds in the treatment of a cognitivedisorder, psychotic disorder, neurotransmitter-mediated disorder or aneuronal disorder.

Articles of manufacture comprising a compound of the invention, or asalt or solvate thereof, in a suitable container are provided. Thecontainer may be a vial, jar, ampoule and the like.

General Description of Biological Assays

The binding properties of compounds disclosed herein to a panel ofaminergic G protein-coupled receptors including adrenergic receptors,dopamine receptors, serotonin receptors, histamine receptors and animidazoline receptor may be determined. Binding properties may beassessed by methods known in the art, such as competitive bindingassays. In one variation, compounds are assessed by the binding assaysdetailed herein. Compounds disclosed herein may also be tested incell-based assays or in in vivo models for further characterization. Inone aspect, compounds disclosed herein are of any formula detailedherein and further display one or more of the following characteristics:inhibition of binding of a ligand to an adrenergic receptor (e.g.,α_(1D), α_(2A) and α_(2B)), inhibition of binding of a ligand to aserotonin receptor (e.g., 5-HT_(2A), 5-HT_(2C), 5-HT₆ and 5-HT₇),inhibition of binding of a ligand to a dopamine receptor (e.g., D_(2L)),and inhibition of binding of a ligand to a histamine receptor (e.g., H₁,H₂ and H₃); agonist/antagonist activity to a serotonin receptor (e.g.,5-HT_(2A), 5-HT₆); agonist/antagonist activity to a dopamine receptor(e.g., D_(2L), D_(2S)); agonist/antagonist activity to a histaminereceptor (e.g., H₁); activity in a neurite outgrowth assay; efficacy ina preclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction; efficacy in a preclinical model of attentionimpulsivity and executive function, and efficacy in a preclinical modelof schizophrenia.

In one variation, inhibition of binding of a ligand to a receptor ismeasured in the assays described herein. In another variation,inhibition of binding of a ligand is measured in an assay known in theart. In one variation, binding of a ligand to a receptor is inhibited byat least about 80% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by greater than about any one of 80%,85%, 90%, 95%, 100%, or between about 85% and about 95% or between about90% and about 100% as determined in a suitable assay known in the artsuch as the assays described herein. In one variation, binding of aligand to a receptor is inhibited by at least about 80%±20% asdetermined in an assay known in the art.

In one variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailed herein(e.g., α_(1D), α_(2A), α_(2B), 5-HT_(2A), 5-HT_(2C), 5-HT₆, 5-HT₇,D_(2L), H₁, H₂, H₃). In one variation, a compound of the inventioninhibits binding of a ligand to at least one receptor and as many aseleven as detailed herein (e.g., α_(1D), α_(2A), α_(2B), 5-HT_(2A),5-HT_(2C), 5-HT₆, 5-HT₇, D₂, H₁, H₂, H₃). In one variation, a compoundof the invention inhibits binding of a ligand to at least one and asmany as eleven receptors detailed herein and further displays agonist orantagonist activity to one or more receptors detailed herein (e.g.,serotonin receptor 5-HT_(2A), serotonin receptor 5-HT₆, dopaminereceptor D_(2L), dopamine receptor D_(2S) and histamine receptor H₁) asmeasured in the assays described herein. In one variation, agonistresponse of serotonin receptor 5-HT_(2A) is inhibited by compounds ofthe invention by at least about any one of 50%, 60%, 70%, 80%, 90%,100%, 110%, 120%, 130%, 140%, 150% as determined in a suitable assaysuch as the assay described herein.

In one variation, a compound of the invention displays the abovedescribed neurotransmitter receptor binding profile, e.g., inhibitsbinding of a ligand to at least one receptor and as many as eleven asdetailed herein and further stimulates neurite outgrowth, e.g., asmeasured by the assays described herein. Certain compounds of theinvention showed activity in neurite outgrowth assays using primaryneurons in culture. Data is presented indicating that a compound of theinvention has activity comparable in magnitude to that of naturallyoccurring prototypical neurotrophic proteins such as brain derivedneurotrophic factor (BDNF) and nerve growth factor (NGF). Notably,neurite outgrowth plays a critical part of new synaptogenesis, which isbeneficial for the treatment of neuronal disorders. In one variation,neuronal disorders include ADHD. In one variation, neurite outgrowth isobserved with a potency of about 1 μM as measured in a suitable assayknown in the art such as the assays described herein. In anothervariation, neurite outgrowth is observed with a potency of about 500 nM.In a further variation, neurite outgrowth is observed with a potency ofabout 50 nM. In another variation, neurite outgrowth is observed with apotency of about 5 nM.

In another variation, a compound of the invention inhibits binding of aligand to at least one receptor and as many as eleven as detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein and further stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein and/or display the above described neurotransmitter receptorbinding profile and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,and in preclinical models of attention/impulsivity and executivefunction, e.g., shows pro-cognitive effects in a preclinical model ofmemory dysfunction. Compounds of the invention have been shown to beeffective in a preclinical model of memory dysfunction associated withcholinergic hypofunction (see relevant Examples). As H₁ antagonism maycontribute to sedation, weight gain and reduced cognition, low affinity(less than about 80% inhibition of binding of Pyrilamine at 1 μM in theassay described herein) for this receptor may be associated withpro-cognitive effects and a more desirable side effect profile.Furthermore, compounds of the invention with increased potency as a5-HT₆ antagonist may have cognition-enhancing effects as serotoninacting through this receptor may impair memory.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction, e.g.,shows pro-cognitive effects in a preclinical model of memorydysfunction, in preclinical models of attention/impulsivity andexecutive function, and further displays agonist or antagonist activityto one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors as detailedherein, further shows efficacy in a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction, e.g.,shows pro-cognitive effects in a preclinical model of memorydysfunction, and in preclinical models of attention/impulsivity andexecutive function, and further stimulates neurite outgrowth.

In another variation, a compound of the invention inhibits at least oneand as many as eleven receptors as detailed herein, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction e.g., shows pro-cognitive effectsin a preclinical model of memory dysfunction, in preclinical models ofattention/impulsivity and executive function, further displays agonistor antagonist activity to one or more receptor detailed herein andfurther stimulates neurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors and furtherpossesses anti-psychotic effects as measured in a preclinical model ofschizophrenia, e.g., shows efficacy in a preclinical model ofschizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further displaysagonist or antagonist activity to one or more receptors detailed herein.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, and in preclinical modelsof attention/impulsivity and executive function, and further showsefficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed hereinand further shows efficacy in a preclinical model of memory dysfunctionassociated with cholinergic dysfunction/hypofunction such as enhancementof memory retention and reduction of memory impairment, and inpreclinical models of attention/impulsivity and executive function.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further stimulatesneurite outgrowth and further shows efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunctionsuch as enhancement of memory retention and reduction of memoryimpairment, and in preclinical models of attention/impulsivity andexecutive function.

In a further variation, a compound of the invention inhibits binding ofa ligand to at least one and as many as eleven receptors detailedherein, further displays agonist or antagonist activity to one or morereceptors detailed herein, further stimulates neurite outgrowth andfurther shows efficacy in a preclinical model of schizophrenia.

In another variation, a compound of the invention inhibits binding of aligand to at least one and as many as eleven receptors, further showsefficacy in a preclinical model of schizophrenia, further displaysagonist or antagonist activity to one or more receptors detailed herein,further stimulates neurite outgrowth and further shows efficacy in apreclinical model of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models ofattention/impulsivity and executive function.

In another variation, a compound of the invention stimulates neuriteoutgrowth. In another variation, a compound of the invention showsefficacy in a preclinical model of schizophrenia and further stimulatesneurite outgrowth. In another variation, a compound of the inventionstimulates neurite outgrowth and further shows efficacy in a preclinicalmodel of memory dysfunction associated with cholinergicdysfunction/hypofunction such as enhancement of memory retention andreduction of memory impairment, and in preclinical models ofattention/impulsivity and executive function. In another variation, acompound of the invention shows efficacy in a preclinical model ofschizophrenia, further stimulates neurite outgrowth and further showsefficacy in a preclinical model of memory dysfunction associated withcholinergic dysfunction/hypofunction such as enhancement of memoryretention and reduction of memory impairment, and in preclinical modelsof attention/impulsivity and executive function.

In one aspect, compounds of the invention inhibit binding of a ligand toadrenergic receptors α_(1D), α_(2A), α_(2B) and inhibit binding of aligand to serotonin receptor 5-HT₆. In another variation, compounds ofthe invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and to any one ormore of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A) and5-HT_(2C). In another variation, compounds of the invention inhibitbinding of a ligand to adrenergic receptors α_(1D), α_(2A), α_(2B), toserotonin receptor 5-HT₆ and to any one or more of the followingreceptors: serotonin receptor 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and furthershow weak inhibition of binding of a ligand to histamine receptor H₁and/or H₂. In one variation, compounds of the invention that alsodisplay strong inhibition of binding of a ligand to the serotoninreceptor 5-HT₇ are particularly desired. In another variation, compoundsof the invention inhibit binding of a ligand to adrenergic receptorsα_(1D), α_(2A), α_(2B), to serotonin receptor 5-HT₆ and further showweak inhibition of binding of a ligand to histamine receptor H₁ and/orH₂. Weak inhibition of binding of a ligand to the histamine H₁ receptoris permitted as agonists of this receptor have been implicated instimulating memory as well as weight gain. In one variation, binding tohistamine receptor H₁ is inhibited by less than about 80%. In anothervariation, binding of a ligand to histamine receptor H₁ is inhibited byless than about any of 75%, 70%, 65%, 60%, 55%, or 50% as determined bya suitable assay known in the art such as the assays described herein.

In another variation, compounds of the invention inhibit binding of aligand to a dopamine receptor D₂. In another variation, compounds of theinvention inhibit binding of a ligand to dopamine receptor D_(2L). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D₂ and to serotonin receptor 5-HT_(2A). Inanother variation, compounds of the invention inhibit binding of aligand to dopamine receptor D_(2L) and to serotonin receptor 5-HT_(2A).In another variation, compounds of the invention inhibit binding of aligand to histamine receptor H₁. In certain aspects, compounds of theinvention further show one or more of the following properties: stronginhibition of binding of a ligand to the serotonin 5-HT₇ receptor,strong inhibition of binding of a ligand to the serotonin 5-HT_(2A)receptor, strong inhibition of binding of a ligand to the serotonin5-HT_(2C) receptor, weak inhibition of binding of a ligand to thehistamine H₁ receptor, weak inhibition of binding of ligands to thehistamine H₂ receptor, and antagonist activity to serotonin receptor5-HT_(2A).

In one variation, compounds of the invention show any of the receptorbinding aspects detailed herein and further display agonist/antagonistactivity to one or more of the following receptors: serotonin receptor5-HT_(2A), serotonin receptor 5-HT₆, dopamine receptor D_(2L), dopaminereceptor D_(2S) and histamine receptor H₁. In one variation, compoundsof the invention show any of the receptor binding aspects detailedherein and further stimulate neurite outgrowth. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in a preclinical model ofmemory dysfunction associated with cholinergic dysfunction/hypofunction,such as enhancement of memory retention and reduction of memoryimpairment and in preclinical models of attention/impulsivity andexecutive function. In one variation, compounds of the invention showany of the receptor binding aspects detailed herein and further showefficacy in a preclinical model of schizophrenia. In one variation,compounds of the invention show any of the receptor binding aspectsdetailed herein and further show efficacy in any one or more ofagonist/antagonist assays (e.g., to serotonin receptor 5-HT_(2A), 5-HT₆,dopamine receptor D_(2L), dopamine receptor D_(2S) and histaminereceptor H₁), neurite outgrowth, a preclinical model of memorydysfunction associated with cholinergic dysfunction/hypofunction and apreclinical model of schizophrenia.

In some aspects, compounds of the invention inhibit binding of a ligandto adrenergic receptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆and a dopamine receptor D₂ by at least about 80% as determined in asuitable assay known in the art such as the assays described herein. Inone variation binding is inhibited by at least about 80% as measured ina suitable assay such as the assays described herein. In some aspects,compounds of the invention inhibit binding of a ligand to adrenergicreceptors α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT₆ and dopaminereceptor D_(2L), by at least about 80% as determined in a suitable assayknown in the art such as the assays described herein. In one variationbinding is inhibited by at least about 80% as measured in a suitableassay such as the assays described herein. In one variation, binding ofa ligand to a receptor is inhibited by greater than about any one of80%, 85%, 90%, 95%, 100%, or between about 85% and about 95% or betweenabout 90% and about 100% as determined in a suitable assay known in theart such as the assays described herein.

In some aspects, compounds of the invention display the above describedneurotransmitter receptor binding profile and further show antipsychoticeffects. It is recognized that compounds of the invention have bindingprofiles similar to compounds with antipsychotic activity and severalcompounds of the invention have been shown to be effective in apreclinical model of schizophrenia (see relevant Examples). In addition,compounds of the invention might possess the cognitive enhancingproperties of dimebon and thus add to the beneficial pharmacologyprofile of these antipsychotic molecules. In one variation, compounds ofthe invention display the above described neurotransmitter receptorbinding profile and further show pro-cognitive effects in a preclinicalmodel of memory dysfunction such as enhancement of memory retention andreduction of memory impairment. In another variation, compounds of theinvention display the above described neurotransmitter receptor bindingprofile and do not show pro-cognitive effects in a preclinical model ofmemory dysfunction, learning and memory.

In one variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory. In a further variation, compounds of the invention possessanti-psychotic effects in a preclinical model of schizophrenia. In afurther variation, compounds of the invention demonstrate pro-cognitiveeffects in a preclinical model of memory dysfunction, learning andmemory and further possess anti-psychotic effects in a preclinical modelof schizophrenia.

Overview of the Methods

The compounds described herein may be used to treat, prevent, delay theonset and/or delay the development of cognitive disorders, psychoticdisorders, neurotransmitter-mediated disorders and/or neuronal disordersin individuals, such as humans. In one aspect, the compounds describedherein may be used to treat, prevent, delay the onset and/or delay thedevelopment of a cognitive disorder. In one variation, cognitivedisorder as used herein includes and intends disorders that contain acognitive component, such as psychotic disorders (e.g., schizophrenia)containing a cognitive component (e.g., CIAS). In one variation,cognitive disorder includes ADHD. In another aspect, the compoundsdescribed herein may be used to treat, prevent, delay the onset and/ordelay the development of a psychotic disorder. In one variation,psychotic disorder as used herein includes and intends disorders thatcontain a psychotic component, for example cognitive disorders (e.g.,Alzheimer's disease) that contain a psychotic component (e.g., psychosisof Alzheimer's Disease or dementia). In one variation, methods ofimproving at least one cognitive and/or psychotic symptom associatedwith schizophrenia are provided. In one aspect, methods of improvingcognition in an individual who has or is suspected of having CIAS areprovided. In a particular aspect, methods of treating schizophrenia areprovided wherein the treatment provides for an improvement in one ormore negative symptom and/or one or more positive symptom and/or one ormore disorganized symptom of schizophrenia. In yet another aspect, thecompounds described herein may be used to treat, prevent, delay theonset and/or delay the development of a neurotransmitter-mediateddisorders disorder. In one aspect, a neurotransmitter-mediated disorderincludes ADHD. In one embodiment, the neurotransmitter-mediated disorderincludes spinal cord injury, diabetic neuropathy, allergic diseases(including food allergies) and diseases involving geroprotectiveactivity such as age-associated hair loss (alopecia), age-associatedweight loss and age-associated vision disturbances (cataracts). Inanother variation, the neurotransmitter-mediated disorder includesspinal cord injury, diabetic neuropathy, fibromyalgia and allergicdiseases (including food allergies). In still another embodiment, theneurotransmitter-mediated disorder includes Alzheimer's disease,Parkinson's Disease, autism, Guillain-Barré syndrome, mild cognitiveimpairment, multiple sclerosis, stroke and traumatic brain injury. Inyet another embodiment, the neurotransmitter-mediated disorder includesschizophrenia, anxiety, bipolar disorders, psychosis, depression andADHD. In one variation, depression as used herein includes and intendstreatment-resistant depression, depression related to a psychoticdisorder, or depression related to a bipolar disorder. In anotheraspect, the compounds described herein may be used to treat, prevent,delay the onset and/or delay the development of a neuronal disorder. Inone aspect, the compounds described herein may also be used to treat,prevent, delay the onset and/or delay the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial.

The invention also provides methods of improving cognitive functionsand/or reducing psychotic effects comprising administering to anindividual in need thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to improve cognitivefunctions and/or reduce psychotic effects. In a particular variation, amethod of treating schizophrenia is provided, wherein the treatmentprovides an improvement in at least one cognitive function, such as animprovement in a cognitive function in an individual who has or issuspected of having CIAS. In a further variation, a method of treatingschizophrenia is provided wherein the method reduces psychotic effectsassociated with schizophrenia. In one embodiment, a method of treatingschizophrenia is provided wherein the method improves the negativesymptoms of schizophrenia in an individual in need thereof. In oneembodiment, a method of treating schizophrenia is provided wherein themethod improves the positive symptoms of schizophrenia in an individualin need thereof. In a further variation, a method of treatingschizophrenia is provided wherein the method both improves cognitivefunction and reduces psychotic effects in an individual in need thereof.A method of improving one or more negative, positive and disorganizedsymptoms of schizophrenia is also provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In one variation, a method of improving at least one negative symptom ofschizophrenia is provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In anothervariation, a method of improving at least one negative and at least onepositive symptom of schizophrenia is provided, where the method entailsadministering a compound as detailed herein, or a pharmaceuticallyacceptable salt thereof, to an individual in need of such improvement.In yet another variation, a method of improving at least one negativeand at least one disorganized symptom of schizophrenia is also provided,where the method entails administering a compound as detailed herein, ora pharmaceutically acceptable salt thereof, to an individual in need ofsuch improvement. In still another variation, a method of improving atleast one positive and at least one disorganized symptom ofschizophrenia is also provided, where the method entails administering acompound as detailed herein, or a pharmaceutically acceptable saltthereof, to an individual in need of such improvement. In still afurther variation, a method of improving at least one negative, at leastone positive and at least one disorganized symptom of schizophrenia isprovided, where the method entails administering a compound as detailedherein, or a pharmaceutically acceptable salt thereof, to an individualin need of such improvement.

The invention also provides methods of stimulating neurite outgrowthand/or promoting neurogenesis and/or enhancing neurotrophic effects inan individual comprising administering to an individual in need thereofan amount of a compound of the invention or a pharmaceuticallyacceptable salt thereof effective to stimulate neurite outgrowth and/orto promote neurogenesis and/or to enhance neurotrophic effects.

The invention further encompasses methods of modulating an aminergic Gprotein-coupled receptor comprising administering to an individual inneed thereof an amount of a compound of the invention or apharmaceutically acceptable salt thereof effective to modulate anaminergic G protein-coupled receptor.

It is to be understood that methods described herein also encompassmethods of administering compositions comprising the compounds of theinvention.

Methods for Treating, Preventing, Delaying the Onset, and/or Delayingthe Development Cognitive Disorders, Psychotic Disorders,Neurotransmitter-mediated Disorders and/or Neuronal Disorders

In one aspect, the invention provides methods for treating, preventing,delaying the onset, and/or delaying the development of cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders for which the modulation of an aminergic Gprotein-coupled receptor is believed to be or is beneficial, the methodcomprising administering to an individual in need thereof a compound ofthe invention. In some variations, modulation of adrenergic receptorα_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆, 5-HT₇,histamine receptor H₁ and/or H₂ is expected to be or is beneficial forthe cognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, modulation ofadrenergic receptor α_(1D), α_(2A), α_(2B) and a serotonin receptor5-HT₆ receptor is expected to be or is beneficial for the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders. In some variations, modulation of adrenergicreceptor α_(1D), α_(2A), α_(2B), and a serotonin receptor 5-HT₆ receptorand modulation of one or more of the following receptors serotonin5-HT₇, 5-HT_(2A), 5-HT_(2C) and histamine H₁ and H₂ is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of dopamine receptor D_(2L) is expected to be oris beneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. In somevariations, modulation of a dopamine receptor D₂ is expected to be or isbeneficial for the cognitive disorders, psychotic disorders,neurotransmitter-mediated disorders and/or neuronal disorders. Incertain variations, modulation of a dopamine D_(2L) receptor andserotonin receptor 5-HT_(2A) is expected to be or is beneficial for thecognitive disorders, psychotic disorders, neurotransmitter-mediateddisorders and/or neuronal disorders. In some variations, the cognitivedisorders, psychotic disorders, neurotransmitter-mediated disordersand/or neuronal disorders are treated, prevented and/or their onset ordevelopment is delayed by administering a compound of the invention.

Methods to Improve Cognitive Functions and/or Reduce Psychotic Effects

The invention provides methods for improving cognitive functions byadministering a compound of the invention to an individual in needthereof. In some variations, modulation of one or more of adrenergicreceptor α_(1D), α_(2A), α_(2B), serotonin receptor 5-HT_(2A), 5-HT₆,5-HT₇, histamine receptor H₁ and/or H₂ is desirable or expected to bedesirable to improve cognitive functions. In some variations modulationof α_(1D), α_(2A), α_(2B) adrenergic receptors and a serotonin 5-HT₆receptor is desirable or expected to be desirable to improve cognitivefunctions. In some variations, modulation of α_(1D), α_(2A), α_(2B)adrenergic receptors and serotonin receptor 5-HT₆ and modulation of oneor more of the following receptors: serotonin receptor 5-HT₇, 5-HT_(2A),5-HT_(2C) and histamine receptor H₁ and H₂, is desirable or expected tobe desirable to improve cognitive functions. In another aspect, theinvention encompasses methods to reduce psychotic effects byadministering a compound of the invention to an individual in needthereof. In some embodiments, modulation of a dopamine D₂ receptor isexpected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor is expected to beor is desirable to reduce psychotic effects. In some embodiments,modulation of a dopamine D₂ receptor and a serotonin 5-HT_(2A) receptoris expected to be or is desirable to reduce psychotic effects. In someembodiments, modulation of a dopamine D_(2L) receptor and a serotonin5-HT_(2A) receptor is expected to be or is desirable to reduce psychoticeffects. In some variations, a compound of the invention is administeredto an individual in need thereof.

Methods to Stimulate Neurite Outgrowth, Promote Neurogenesis and/orEnhance Neurotrophic Effects

In a further aspect, the invention provides methods of stimulatingneurite outgrowth and/or enhancing neurogenesis and/or enhancingneurotrophic effects comprising administering a compound of theinvention or pharmaceutically acceptable salt thereof under conditionssufficient to stimulate neurite outgrowth and/or to enhance neurogenesisand/or enhance neurotrophic effects to an individual in need thereof. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 1 μM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 500 nMas measured in a suitable assay such as the assays described herein. Insome variations, a compound of the invention stimulates neuriteoutgrowth at a potency of about 50 nM as measured in a suitable assaysuch as the assays described herein. In some variations, a compound ofthe invention stimulates neurite outgrowth at a potency of about 5 nM asmeasured in a suitable assay such as the assays described herein.

Methods to Modulate an Aminergic G Protein-Coupled Receptor

The invention further contemplates methods for modulating the activityof an aminergic G-protein-coupled receptor comprising administering acompound of the invention or pharmaceutically acceptable salt thereofunder conditions sufficient to modulate the activity of an aminergic Gprotein-coupled receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ receptor. In some variations, the aminergic Gprotein-coupled receptor is a α_(1D), α_(2A), α_(2B) adrenergic receptorand a serotonin 5-HT₆ and 5-HT₇ receptor. In some variations, theaminergic G protein-coupled receptor is a α_(1D), α_(2A), α_(2B)adrenergic receptor, a serotonin 5-HT₆ and one or more of the followingreceptors: serotonin 5-HT₇, 5-HT_(2A) and 5-HT_(2C) and histamine H₁ andH₂ receptor. In some variations, the aminergic G protein-coupledreceptor is a dopamine D₂ receptor. In some variations, the aminergic Gprotein-coupled receptor is a dopamine D_(2L), receptor. In somevariations, the aminergic G protein-coupled receptor is a dopamine D₂receptor and a serotonin 5-HT_(2A) receptor. In some variations, theaminergic G protein-coupled receptor is a dopamine D_(2L) receptor and aserotonin 5-HT_(2A) receptor. In some variations, the aminergic Gprotein-coupled receptor is a histamine H₁ receptor.

General Synthetic Methods

The compounds of the invention may be prepared by a number of processesas generally described below and more specifically in the Exampleshereinafter. In the following process descriptions, the symbols whenused in the formulae depicted are to be understood to represent thosegroups described above in relation to the formulae herein.

Where it is desired to obtain a particular enantiomer of a compound,this may be accomplished from a corresponding mixture of enantiomersusing any suitable conventional procedure for separating or resolvingenantiomers. Thus, for example, diastereomeric derivatives may beproduced by reaction of a mixture of enantiomers, e.g. a racemate, andan appropriate chiral compound. The diastereomers may then be separatedby any convenient means, for example by crystallization and the desiredenantiomer recovered. In another resolution process, a racemate may beseparated using chiral High Performance Liquid Chromatography.Alternatively, if desired a particular enantiomer may be obtained byusing an appropriate chiral intermediate in one of the processesdescribed.

Chromatography, recrystallization and other conventional separationprocedures may also be used with intermediates or final products whereit is desired to obtain a particular isomer of a compound or tootherwise purify a product of a reaction.

The following abbreviations are used herein: thin layer chromatography(TLC); hour (h); minute (min); second (sec); ethanol (EtOH);dimethylsulfoxide (DMSO); dimethylformamide (DMF); trifluoroacetic acid(TFA); tetrahydrofuran (THF); Normal(N); aqueous (aq.); methanol (MeOH);dichloromethane (DCM); ethyl acetate (EtOAc); Retention factor (Rf);room temperature (RT).

General methods of preparing compounds according to the invention aredepicted in exemplified methods below. Other compounds of the inventionmay be prepared by similar methods. Synthetic methods to provide similarintermediates have also been described in, for example, PCT PatentApplication Nos. PCT/US2008/081390, PCT/US2009/032065,PCT/US2009/038142, PCT/US2009/038138, PCT/US2010/050078,PCT/US2010/050079 and PCT/US2010/050081. Synthetic methods to provideazepino[4,5-b]indole intermediates have been described in PCTApplication No. PCT/US2009/062872. Synthetic methods to provide bicyclopyrido[3,4-b]indoles have been described in PCT Application No.PCT/US/2010/050080. The experimental details of each of theseapplications are incorporated herein by reference.

Exemplified routes to synthesizing particular compounds of the inventionare shown below as General Methods 1 to 5.

General Method 1.

Step 1: Preparation of Compound 1-B.

A solution of 4-chloro-2-bromophenyl hydrazine hydrochloride (15 g, 58mmol) and 1-methylpiperidin-4-one (6.57 g, 58 mmol) in 7% H₂SO₄ indioxane (150 mL) is stirred at 80° C. for 5 h. The progress of reactionis monitored by TLC. The reaction mixture is concentrated under reducedpressure to dryness. The residue is basified with aq. NaOH solution andextracted with EtOAc. The organic layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crude product,which is purified by column chromatography (7% MeOH-DCM) to yieldcompound 1-B (7.6 g).

Step 2: Preparation of Compound 1-C.

A stirred solution of6-bromo-8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole(1-B) (200 mg, 0.667 mmol) in DMF (2 mL) is cooled to −78° C., followedby addition of sodium hydride (20 mg, 0.800 mmol) and methyl iodide (2Min DMF, 0.3 mL, 0.60 mmol). The reaction mixture is stirred at −78° C.for 5 min. Ice-water is added into the reaction mixture and the mixtureis then extracted with EtOAc (2×10 mL). The combined organic layer isdried over anhydrous sodium sulfate and concentrated under reducedpressure to afford crude material, which is purified by columnchromatography using silica (100:200 mesh) and 0-4% MeOH:DCM to yieldcompound 1-C (38 mg).

Step 3: Preparation of Compound 1-D.

A mixture of6-bromo-8-chloro-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-C) (210 mg, 0.670 mmol), copper(I)iodide (1.3 mg, 0.007 mmol),dichlorobis(triphenylphosphine) palladium(II) (24 mg, 0.034 mmol) isevacuated and back filled with nitrogen. Triethylamine (2.5 mL) isadded, followed by dropwise addition of ethynyltriisopropylsilane (146mg, 0.804 mmol). The reaction mixture is stirred at 85° C. overnight.Water is added into the reaction mixture and the mixture is thenextracted with EtOAc. The organic layer is dried over anhydrous sodiumsulfate and concentrated under reduced pressure to afford crudematerial, which is purified by column chromatography using silica(100:200 mesh) and 0-4% MeOH:DCM to yield compound 1-D (218 mg).

Step 4: Preparation of Compound 1-E.

To an ice cooled stirred solution of8-chloro-2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-D) (212 mg, 0.512 mmol) in dry THF (10 mL) is addedtetrabutylammoniumfluoride (1M solution in THF, 1.638 mL, 1.638 mmol).The reaction mixture is allowed to warm to RT and stirring continued for15 min. Water is added into the reaction mixture and the mixture isextracted with EtOAc (2×25 mL). The organic layer is dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford compound 1-E (166 mg).

Step 5: Preparation of Compound 1-F.

A mixture of8-chloro-6-ethynyl-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole(1-E) (166 mg, 0.642 mmol), 5-bromo-2-methylpyridine (132 mg, 0.770mmol), dichlorobis(triphenyl phosphine)palladium (II) (23 mg, 0.032mmol) and copper (I) iodide (1.1 mg, 0.006 mmol) is evacuated and backfilled with nitrogen. Triethylamine (2 mL) is added dropwise undernitrogen atmosphere. The reaction mixture is stirred at 85° C.overnight. Triethylamine is evaporated under reduced pressure. Theresidue is dissolved in water (10 mL) and extracted with EtOAc (2×25mL). The organic layer is washed with water (2×10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crude material, which is purified by column chromatography usingneutral alumina and 0-8% MeOH-EtOAc, followed by reverse phase HPLC toyield compound 1-F as the free base (16.23 mg).

General Method 2.

Step 1: Preparation of Compound 2-B.

To a suspension of 2-chlorophenyl hydrazine hydrochloride (2-A) (19.7 g,0.110 mol) in dioxane (190 mL) is dropwise added conc. H₂SO₄ (8 mL,0.150 mol). After stirring for 10 min, N-methyl-4-piperidone (17.53 g,0.154 mol) is added into the reaction mixture and stirring continued atRT for 20 min. The reaction mixture is then stirred at 80° C. for 4 h.The progress of reaction is monitored by TLC. The solvent is removedunder reduced pressure and the pH of the residue adjusted to pH 8-9 byaddition of saturated sodium bicarbonate solution. The aqueous layer isextracted with EtOAc (3×300 mL). The combined organic layer is washedwith water, followed by brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure to afford crude material, which ispurified by re-crystallization (Ether/Hexane) to yield compound 2-B as abrown solid (7.5 g).

Step 2: Preparation of Compound 2-C.

To a degassed mixture of6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (2-B) (100mg, 0.5 mmol), sodium tert-butoxide (576 mg, 6.0 mmol), palladiumacetate (22.4 mg, 0.1 mmol) and 2,4di-tert-butylphosphino-2′,4′,6′-triisopropyl biphenyl (63.0 mg, 0.15mmol) is added dry toluene (2 mL). After stirring for 5 min,benzylmethylamine (0.09 mL, 0.7 mmol) is added to the reaction mixture,which is stirred at 100° C. for 16 h. The reaction mixture is filteredand the residue washed with EtOAc. The filtrate is concentrated underreduced pressure to afford crude material, which is purified by reversephase HPLC to yieldbenzyl-methyl-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl)-amine(2-C) (50 mg).

General Method 3.

Alcohol compounds of type 3-C can be prepared from the bromo precursor3-A by treatment with epoxide 3-B under standard Grignard orGrignard-cuprate coupling conditions known to those skilled in the art.Fluorination of 3-C with agents such as Diethylaminosulfur-trifluoride(DAST) provides the fluoro derivative 3-D. Alternatively, treatment of3-A with alkene 3-E under Heck coupling conditions affords the styrylproduct of the type 3-F. Alternative coupling conditions includingStille and Suzuki, and the like, using corresponding reagents, will befamiliar to those skilled in the art.

General Method 4.

Condensation of appropriately functionalized 4-hydrazino pyridine E-1with functionalized azepan-4-ones in step 1 yields the9-aza-hexahydroazepino[5,4-b]indole intermediate E-2. The indolenitrogen atom at this stage can be functionalized in step 2 with alkylgroups (W) or protected with various protecting groups (PG) known tothose skilled in the art to give E-3. Subjecting E-3 to alkyne couplingconditions with triisopropyl (TIPS) acetylene yields the adduct E-4, theTIPS group of which can be cleaved under standard silane-deprotectionchemistry to afford alkyne E-5. Oxidation of the triple bond of E-5 instep 5 provides aldehyde E-6, which can be treated in step 6 with anaryl lithium or aryl Grignard reagent to yield the alcohol product E-7.Halo intermediate E-3 can alternatively be treated under aryl couplingconditions such as, for example, the Heck reaction in step 7 to giveproduct E-8, the styrene double bond of which can be hydrated in step 8to give the tertiary alcohol product E-9. An alternative coupled productto E-4 can be obtained in step 9 through coupling of compound E-9 withappropriately functionalized aryl acetylenes to get alkyne E-10.Although the Scheme depicts phenyl or pyridyl rings in the compounds, itis understood that a number of aromatic and heteroaromatic analogs areconceivable for such synthetic routes, including but not limited topyrimidine, pyrazine, thiophene, furan, pyrrolo, imidazole, thiazole,and the like. Similarly, the point of attachment of groups such as R′ tothe aromatic or heteroaromatic groups can be envisioned in a variety ofchemically feasible locations. All possible attachment locations offunctional groups on the aromatic ring(s) should be considered.

General Method 5.

Condensation of appropriately functionalized aryl hydrazine G-1 withcyclohexane-1,3-dione in step 1 yields the dihydrocarbazoloneintermediate G-2. The keto group is then converted in step 2 usingstandard conditions to give oxime G-3 that can undergo a Beckmannrearrangement in step 3 to yield the tetrahydroazepinoindolone G-4.Reduction of the amide in step 4 provides hexahydroazepinoindole G-5,the secondary amino group of which can be functionalized in step 5 toprovide functionalized tertiary amine G-6. The indole nitrogen atom atthis stage can be functionalized in step 6 with alkyl groups (W) orprotected with various protecting groups (PG) known to those skilled inthe art to give G-7. At this stage, a number of options are appropriateherein for G-7. Subjecting G-7 to alkyne coupling conditions in step 7with triisopropyl (TIPS) acetylene yields the adduct G-8, the TIPS groupof which can be cleaved in step 8 under standard silane-deprotectionchemistry to afford alkyne G-9. Oxidation of the triple bond of G-9 instep 9 provides aldehyde G-10, which can be treated in step 10 with, forexample, an aryl lithium or aryl Grignard reagent to yield the alcoholproduct G-11. Halo intermediate G-7 can alternatively be treated underaryl coupling conditions such as, for example, the Heck reaction in step11 to give product G-12, the styrene double bond of which can behydrated in step 12 to give the tertiary alcohol product G-13. Analternative coupled product to G-8 can be obtained in step 13 throughcoupling of compound G-7 with appropriately functionalized arylacetylenes to get alkyne G-14. Although the Scheme depicts phenyl orpyridyl rings in the compounds, it is understood that a number ofaromatic and heteroaromatic analogs are conceivable for such syntheticroutes, including but not limited to pyrimidine, pyrazine, thiophene,furan, pyrrolo, imidazole, thiazole, and the like. Similarly, the pointof attachment of groups such as R′ to the aromatic or heteroaromaticgroups can be envisioned in a variety of chemically feasible locations.All possible attachment locations of functional groups on the aromaticring(s) should be considered.

Representative compounds of the invention are shown in Table 1.

TABLE 1 Representative Compounds of the Invention Com- pound No.Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

One or more of the General Methods detailed above may be adapted orcombined as required by those of skill in the art to make compoundsdetailed herein. Particular examples of each of the General Methods areprovided in the Examples below. Compounds 1-18 and 43-44 were preparedaccording to Examples 1-18 and 19-20 respectively.

The following Examples are provided to illustrate but not to limit theinvention.

All references disclosed herein are incorporated by reference in theirentireties.

EXAMPLES Example 1 Preparation of Compound No. 1

To a degassed mixture of6-chloro-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.5mmol), sodium tert-butoxide (576 mg, 6.0 mmol), palladium acetate (22.4mg, 0.1 mmol) and 2,4 di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (63.0 mg, 0.15 mmol) was added dry toluene (2 mL). Afterstirring for 5 min, benzylmethylamine (0.09 mL, 0.7 mmol) was added tothe reaction mixture, which was stirred at 100° C. for 16 h. Thereaction mixture was filtered and residue washed with EtOAc. Thefiltrate was concentrated under reduced pressure to afford crudematerial, which was purified by reverse phase HPLC to yieldbenzyl-methyl-(2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl)-amine(50 mg). ¹H NMR (Freebase, CDCl₃) δ (ppm): 7.80 (bs, 1H), 7.38 (m, 4H),7.28 (m, 1H), 7.10 (s, 1H), 7.0 (t, 1H), 6.78 (d, 1H), 4.28 (s, 2H),3.70 (s, 2H), 2.86 (m, 4H), 2.78 (s, 3H), 2.58 (s, 3H).

Example 2 Preparation of Compound No. 2

To a stirred solution of2,8-dimethyl-6-((6-methylpyridin-3-yl)ethynyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole(1.555 g, 4.936 mol) in dry MeOH (20 ml) was added ammonium formate(1.25 g, 19.74 mmol) and 10% dry Pd—C (200 mg, 1.88 mmol) under argon.The reaction mixture was stirred at 70° C. for 45 min. The reaction wasmonitored by LCMS and TLC. After completion, the solvent was evaporatedunder reduced pressure to yield the title compound. ¹H NMR (TFA salt,CD₃OD) δ (ppm): 8.4 (d, 1H), 8.2 (d, 1H), 7.78 (dd, 1H), 7.1 (s, 1H),6.78 (s, 1H), 4.6 (m, 1H), 4.38 (m, 1H), 3.84 (m, 1H), 3.6 (m, 1H),3.1-3.2 (m, 6H), 2.7-2.8 (m, 9H).

Example 3 Preparation of Compound No. 3

6-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.5 g, 2.27mmol), sodium tert-butoxide (1.30 g, 13.6 mmol), Palladium acetate(0.126 g, 0.453 mmol) and 2-di-tert-butyl-phosphino-2′,4′,6′-triisopropyl-biphenyl (0.193 g, 0.454 mmol) were added to areaction bottle which was evacuated and back filled with nitrogen for 5min followed by addition of dry toluene (20 mL) under nitrogen.Phenylmethanamine (346 mg, 3.24 mmol) was added and the reaction mixturewas heated at 85° C. overnight. The reaction mixture was filtered andwashed with EtOAc (2×25 mL). The filtrate was concentrated and the crudeproduct was purified on neutral alumina using 0-10% MeOH: DCM as eluantto yield 250 mg of the title compound as the free base. ¹H NMR (HClsalt, CD₃OD) δ (ppm): 7.18-7.23 (m, 6H), 7.1 (dd, 1H), 6.8 (d, 1H), 4.76(d, 1H), 4.68 (s, 2H), 4.4 (d, 1H), 3.9 (m, 1H), 3.6 (m, 1H), 3.23 (m,2H), 3.14 (s, 3H).

Example 4 Preparation of Compound No. 4

6-Chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole (0.5 g, 2.27mmol), sodium tert-butoxide (1.30 g, 1.36 mmol), Palladium-acetate(0.101 g, 0.453 mmol) and 2-di-tert-butyl-phosphino-2′,4′,6′-triisopropyl-biphenyl (0.192 g, 0.45 mmol) were added to areaction bottle which was evacuated and back filled with nitrogen for 5min followed by addition of dry toluene (3 mL) under nitrogenatmosphere. (Pyridin-4-yl)methanamine (291 mg, 2.72 mmol) was added andthe reaction mixture was heated at 85° C. overnight. The reactionmixture was filtered and washed with EtOAc (2×25 mL). The filtrate wasconcentrated and the crude product was purified on neutral alumina using0-10% MeOH:EtOAc as eluant to yield 180 mg of the title compound as thefree base. ¹H NMR (Tri-HCl salt, CD₃OD) δ (ppm): 8.79 (d, 2H), 8.1 (d,2H), 6.8 (m, 2H), 6.2 (d, 1H), 4.68 (d, 1H), 4.35 (d, 1H), 3.82 (m, 2H),3.6 (m, 2H), 3.2 (m, 2H), 3.15 (s, 3H).

Example 5 Preparation of Compound No. 5

6-Ethynyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg,0.223 mmol), 4-bromopyridinehydrochloride (52 mg, 0.268 mmol),dichlorobis(triphenylphosphinepalladium(II) (7.82 mg, 0.0093 mmol) wereadded to a reaction bottle which was evacuated and back filled withnitrogen. Triethylamine (5 mL) was added dropwise under nitrogenatmosphere. The reaction mixture was stirred at 100° C. overnight.Triethylamine was removed under reduced pressure. Water (10 mL) wasadded to the residue and the mixture extracted into EtOAc (2×25 mL). Theorganic layer was washed with water (2×10 mL), dried and concentrated.The crude mixture was purified by reverse phase HPLC to yield 4 mg ofthe title compound as the free base. ¹H NMR (Freebase, CDCl₃) δ (ppm):8.62 (d, 2H), 7.4 (d, 2H), 7.21 (s, 1H), 7.2 (s, 1H), 3.8 (s, 2H), 3 (s,2H), 2.6 (m, 5H), 2.4 (s, 3H).

Example 6 Preparation of Compound No. 6

6-Ethynyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg,0.223 mmol), 5-bromo-2-methylpyridine (46 mg, 0.268 mmol) anddichlorobis(triphenylphosphinepalladium(II) (7.82 mg, 0.0093 mmol) wereadded to a reaction bottle which was evacuated and back filled withnitrogen. Triethylamine (5 mL) was added dropwise under nitrogenatmosphere. The reaction mixture was stirred at 100° C. overnight.Triethylamine (5 mL) was added dropwise under nitrogen atmosphere. Thereaction mixture was stirred at 100° C. overnight. Triethylamine wasremoved under reduced pressure. Water (10 mL) was added to the residueand the mixture extracted into EtOAc (2×25 mL). The organic layer waswashed with water (2×10 mL), dried and concentrated. The crude mixturewas purified by reverse phase HPLC to yield 9 mg of the title compoundas the free base. ¹H NMR (Freebase, CDCl₃) δ (ppm): 8.7 (s, 1H), 8.05(s, 1H), 7.75 (d, 1H), 7.21 (s, 1H), 7.2 (m, 2H), 3.7 (s, 2H), 3.0-2.8(m, 4H), 2.60 (s, 6H), 2.41 (s, 3H).

Example 7 Preparation of Compound No. 7

A solution of6-bromo-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (60mg, 0.20 mmol), tetrakis(triphenylphosphine)palladium(0) (11.8 mg,0.0102 mmol) in DME (4 mL) was purged with nitrogen. K₂CO₃ (27.5 mg,0.20 mmol), 4-fluorophenylboronicacid (57.1 mg, 0.41 mmol) and water (2mL) were added followed by nitrogen purging for 2 min. The reactionmixture was stirred at 85° C. for 45 min. EtOAc (10 mL) was added to thereaction mass. The organic layer was washed with water (2×5 mL) andconcentrated. The crude product was purified by column chromatographyusing 100:200 silica gel and 0-5% MeOH-DCM as eluant to yield 37 mg ofthe title compound as the free base. ¹H NMR(HCl salt, CD₃OD) δ (ppm):7.41 (m, 2H), 7.17-7.25 (m, 3H), 6.81 (s, 1H), 4.39 (m, 2H), 3.82 (m,2H), 3.59 (m, 2H), 3.20 (m, 6H), 2.42 (s, 3H).

Example 8 Preparation of Compound No. 8

6-Ethynyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (50 mg,0.223 mmol), 2-bromothiophene (40 mg, 0.24 mmol) anddichlorobis(triphenylphosphinepalladium(II) (7.82 mg, 0.0093 mmol) wereadded to a reaction bottle which was evacuated and back filled withnitrogen. Triethylamine (5 mL) was added dropwise under nitrogenatmosphere and the reaction mixture stirred at 100° C. overnight.Triethylamine was removed under reduced pressure. Water (10 mL) wasadded to the residue and the mixture extracted with EtOAc. The organiclayer was washed with water (2×10 mL), dried over anhydrous sodiumsulfate and concentrated to obtain crude material which was purified byreverse phase HPLC to yield 37 mg of the title compound. ¹H NMR(Freebase, CDCl₃) δ (ppm): 8.17 (s, 1H), 7.37 (m, 2H), 7.21 (s, 1H),7.19 (s, 1H), 7.04 (m, 1H), 3.80 (s, 2H) 3.0 (s, 3H), 2.60 (m, 2H), 2.40(s, 3H).

Example 9 Preparation of Compound No. 9

A solution of6-bromo-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (100mg, 0.85 mmol), tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.0175mmol) in DME (4 mL) was purged with nitrogen. K₂CO₃ (48 mg, 0.35 mmol)and pyridine-4-boronicacid (86 mg, 0.70 mmol) and water (2 mL) wereadded followed by nitrogen purging for 2 min. The reaction mixture wasstirred at 85° C. for 45 min and then diluted with EtOAc (20 mL). Theorganic layer was washed with water (2×5 mL), dried over anhydroussodium sulfate and concentrated. The crude product was purified bycolumn chromatography using 100:200 silica gel and 0-7% MeOH: DCM aseluant to yield 70 mg of the title compound as the free base. ¹H NMR(D1-HCl salt, CD₃OD) δ (ppm): 8.90 (d, 2H), 8.18 (d, 2H), 7.50 (s, 1H),7.08 (s, 1H), 4.79 (d, 1H), 4.40 (d, 1H), 3.86 (m, 1H), 3.60 (m, 1H),3.37 (s, 3H), 3.21 (d, 2H), 3.18 (s, 3H), 2.42 (s, 3H).

Example 10 Preparation of Compound No. 10

To an ice cooled stirred solution of2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5,8-trimethyl-1H-pyrido[4,3-b]indole(1.6 g, 4.06 mmol) n dry THF (10 mL) was dropwise addedtetrabutylammoniumfluoride (1M solution in THF) (13 mL, 13 mmol). Thereaction mixture was allowed to warm up to RT and stirred for 15 min.Water was added to the reaction mixture and passed through Celitefollowed by washing with EtOAc (2×25 mL). The organic layer was washedwith water, dried over sodium sulfate and concentrated. The titlecompound (280 mg) was obtained by recrystallization in hexane. ¹H NMR(Freebase, CDCl₃) δ (ppm): 7.19 (s, 1H), 7.16 (s, 1H), 4.0 (s, 2H), 3.40(s, 2H), 3.21 (s, 1H), 2.82 (s, 5H), 2.57 (s, 3H), 2.38 (s, 3H).

Example 11 Preparation of Compound No. 11

A solution of6-bromo-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (200mg, 0.694 mmol), tetrakis(triphenylphosphine)palladium(0) (40 mg, 0.035mmol) in DME (16 mL) was purged with nitrogen. K₂CO₃ (96 mg, 0.694mmol),4-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)pyridine(672 mg, 2.776 mmol) and water (8 mL) were added followed by nitrogenpurging. The reaction mixture was stirred at 85° C. for 45 min. EtOAc(20 mL) was added to the reaction mixture and washed with water (2×5mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated. The crude product was purified by column chromatographyusing 100:200 silica gel and 0-9% MeOH:DCM as eluant to yield 60 mg ofthe title compound as the free base. ¹H NMR (D1-HCl salt, CD₃OD) δ(ppm): 8.57 (d, 2H), 7.80 (d, 2H), 7.60 (s, 1H), 7.18 (s, 1H), 6.40 (s,1H), 4.62 (d, 1H), 4.31 (d, 1H), 3.98 (s, 3H), 3.89 (m, 1H), 3.60 (m,1H), 3.20 (m, 2H), 3.11 (s, 3H), 2.42 (s, 3H), 2.18 (s, 3H).

Example 12 Preparation of Compound No. 12

6-Ethynyl-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (50mg, 0.152 mmol), 5-bromo-2-methylpyridine (31 mg, 0.182 mmol),dichlorobis(triphenylphosphine)palladium(II) (7.82 mg, 0.0093 mmol) andcopper (I) iodide (1.9 mg, 0.0152 mmol) were charged in a reactionbottle which was evacuated and back filled with nitrogen. Triethylamine(5 mL) was added dropwise under nitrogen atmosphere. The reactionmixture was stirred at 85° C. overnight. Triethylamine was removed underreduced pressure. Water was added to the residue, extracted into EtOAc(2×25 mL) and washed with water (2×10 mL). The organic layer was dried,concentrated and the crude mixture purified by column chromatographyusing neutral alumina and 0-2% MeOH: DCM as eluant to yield 66 mg of thetitle compound as the free base. ¹H NMR (Freebase, CDCl₃) δ (ppm): 8.62(s, 1H), 7.70 (d, 1H), 7.20 (m, 3H), 4.08 (s, 3H), 3.63 (s, 2H), 2.82(s, 4H), 2.60 (d, 6H), 2.40 (s, 3H).

Example 13 Preparation of Compound No. 13

To a solution of2,3,4,5-tetrahydro-2,5,8-trimethyl-6-(2-(6-methylpyridin-3-yl)ethynyl)-1H-pyrido[4,3-b]indole(60 mg, 0.182 mmol) in MeOH (2 mL) were added 10% Pd/C (50 mg) andammonium formate (57.4 mg, 0.91 mmol) followed by nitrogen purging. Thereaction mixture was heated at 70° C. for 5 min. The solid mass wasfiltered under vacuum and washed with MeOH (2×5 mL). The filtrate wasconcentrated and crude product purified by reverse phase HPLC to yield10 mg of the title compound as the TFA salt. ¹H NMR (TFA salt, CD₃OD) δ(ppm): 8.40 (s, 1H), 8.21 (d, 1H), 7.80 (d, 1H), 7.16 (s, 1H), 6.63 (s,1H), 4.63 (d, 1H), 4.24 (d, 1H), 3.91 (m, 4H), 3.58 (m, 1H), 3.41 (m,2H), 3.20 (m, 4H), 3.12 (s, 3H), 2.78 (s, 3H), 2.38 (s, 3H).

Example 14 Preparation of Compound No. 14

To a solution of2,3,4,5-tetrahydro-2,5,8-trimethyl-6-(2-(6-methylpyridin-3-yl)ethynyl)-1H-pyrido[4,3-b]indole(60 mg, 0.182 mmol) in MeOH (2 mL) were added 10% Pd/C (50 mg) andammonium formate (57.4 mg, 0.91 mmol) followed by nitrogen purging. Thereaction mixture was heated at 70° C. for 5 min. The solid mass wasfiltered under vacuum and washed with MeOH (2×5 mL). The filtrate wasconcentrated and crude product purified by reverse phase HPLC to yield3.18 mg of the title compound as the TFA salt. ¹H NMR (TFA salt, CD₃OD)δ (ppm): 8.38 (s, 1H), 8.02 (d, 1H), 7.60 (m, 2H), 7.23 (s, 1H), 6.83(d, 1H), 6.77 (s, 1H), 4.70 (d, 1H), 4.38 (d, 1H), 3.83 (m, 1H), 3.80(s, 3H), 3.60 (m, 1H), 3.20 (m, 2H), 3.18 (s, 3H), 2.64 (s, 3H), 2.30(s, 3H).

Example 15 Preparation of Compound No. 15

To a de-aerated solution of6-bromo-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (100mg, 0.341 mmol) and tetrakis(triphenylphosphine)palladium(0) (20 mg,0.017 mmol) in DME (8 mL) were added potassium carbonate (47 mg, 0.341mmol),2-methyl-5-(1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-1-en-2-yl)pyridine(176 mg, 0.682 mmol) and water (4 mL). The solution was purged withnitrogen and stirred at 85° C. for 45 min. The organic mixture wasextracted with EtOAc (20 mL) and washed with water (2×5 mL). The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The crude obtained was purified by columnchromatography using silica gel (100:200) and 0-8% MeOH-DCM as eluent toyield 66 mg of the desired compound as the free base. ¹H NMR(HCl salt,CD₃OD) δ (ppm): 8.86 (s, 1H), 8.78 (dd, 1H), 7.97 (d, 1H), 7.70 (s, 1H),7.21 (s, 1H), 6.83 (s, 1H), 4.71 (d, 1H), 4.38 (d, 1H), 3.90 (m, 1H),3.81 (s, 3H), 3.60 (m, 1H), 3.2 (m, 2H), 3.17 (s, 3H), 2.83 (s, 3H),2.41 (s, 3H), 2.18 (s, 3H).

Example 16 Preparation of Compound No. 16

6-Ethynyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (137mg, 0.616 mmol), 2-bromothiazole (120 mg, 0.734 mmol) anddichlorobis(triphenylphosphinepalladium (II) (21.43 mg, 0.0306 mmol)were charged in a reaction bottle, which was evacuated and back filledwith nitrogen. Triethylamine (2 mL) was added dropwise under nitrogenatmosphere. The reaction mixture was stirred at 100° C. overnight.Triethylamine was evaporated and water (10 mL) was added to the reactionmixture. The organic mixture was extracted into EtOAc (2×25 mL) andwashed with water (2×10 mL). The organic layer was dried over anhydroussodium sulfate and concentrated under reduced pressure to afford crude,which was purified by reverse phase HPLC. ¹H NMR (HCl salt, CD₃OD) δ(ppm): 7.9 (d, 1H), 7.78 (d, 1H), 7.4 (s, 1H), 7.23 (s, 1H), 4.5 (m,4H), 3.7 (m, 2H), 3.18 (s, 3H), 2.43 (s, 3H).

Example 17 Preparation of Compound No. 17

6-Ethynyl-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (135mg, 0.567 mmol), 4-bromopyridine (107 mg, 0.680 mmol),dichlorobis(triphenylphosphinepalladium(II) (20 mg, 0.028 mmol) andcopper (I) iodide (1 mg, 0.06 mmol) were added to a reaction bottle,which was evacuated and back filled with nitrogen. 1,4-Dioxane (3 mL)was added dropwise into the reaction mixture under nitrogen at 0° C. andstirred the solution at 0° C. for 5 min. Ice water was added to thereaction mixture and the organic mixture was extracted with EtOAc (2×25mL). The organic layer was dried over sodium sulfate, concentrated underreduced pressure and residue obtained was purified by columnchromatography using neutral alumina and 0-2% MeOH:DCM as eluant,followed by reverse phase HPLC purification to yield 11.2 mg of thedesired compound as the free base. ¹H NMR (Freebase, CD₃OD) δ (ppm):8.57 (d, 2H), 7.5 (d, 2H), 7.22 (s, 1H), 7.18 (s, 1H), 4.1 (s, 3H), 3.8(s, 2H), 3.1 (t, 2H), 2.9 (t, 2H), 2.64 (s, 3H), 2.4 (s, 3H).

Example 18 Preparation of Compound No. 18

A mixture of8-chloro-6-ethynyl-2,3,4,5-tetrahydro-2,5-dimethyl-1H-pyrido[4,3-b]indole(166 mg, 0.642 mmol), 5-bromo-2-methylpyridine (132 mg, 0.770 mmol),dichlorobis (triphenylphosphine)palladium (II) (23 mg, 0.032 mmol) andcopper (I) iodide (1.1 mg, 0.006 mmol) was evacuated and back filledwith nitrogen. Triethylamine (2 mL) was added dropwise under nitrogenatmosphere. The reaction mixture was stirred at 85° C. overnight.Triethylamine was evaporated under reduced pressure. The residue wasdissolved in water (10 mL) and the mixture extracted with EtOAc (2×25mL). The organic layer was washed with water (2×10 mL), dried overanhydrous sodium sulfate and concentrated under reduced pressure toafford crude material, which was purified by column chromatography usingneutral alumina and 0-8% MeOH-EtOAc, followed by reverse phase HPLC toyield the desired compound as the free base (16.23 mg). ¹H NMR(Freebase, CDCl₃) δ (ppm): 8.62 (s, 1H), 7.68 (d, 1H), 7.34 (s, 1H), 7.3(s, 1H), 7.18 (d, 1H), 4.03 (s, 3H), 3.78 (s, 2H), 3.0 (t, 2H), 2.9 (t,2H), 2.6 (s, 6H).

Example 19 Preparation of Compound No. 43

To a degassed mixture of6-bromo-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (93 mg,0.33 mmol), ethynyl triisopropylsilane (121 mg, 0.66 mmol) andtriethylamine (2 mL) were added CuI (6.27 mg, 0.033 mmol) anddichlorobis(triphenylphosphine)-palladium(II) (11.5 mg, 0.017 mmol). Thereaction mixture was again degassed using N₂ and stirred at 85° C. for15 h. The progress of reaction was monitored by TLC and LCMS. Thevolatiles were removed under reduced pressure. The residue was dilutedwith water (10 mL) and extracted with DCM (2×50 mL). The organic layerwas dried over anhydrous sodium sulfate and concentrated to yield thedesired compound (100 mg), which was used in the next reaction withoutfurther purification.

To an ice-cooled stirred solution of2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5,8-trimethyl-1H-pyrido[4,3-b]indole(1.2 g, 3.16 mmol) in dry THF (10 mL) was added dropwisetetrabutylammonium fluoride (1M solution in THF, 10 mL). The reactionmixture was allowed to warm to RT and stirred at RT for 15 min. Thereaction mixture was diluted with water and extracted with EtOAc (2×25mL). The organic layer was dried over anhydrous sodium sulfate andconcentrated. The residue was purified by silica gel columnchromatography (Methanol:DCM) to yield the title compound (604 mg).

To an ice-cooled stirred solution of BH₃.DMS complex (1.27 mL, 13.393mmol) in dry THF (10 mL) was added dropwise a solution of pyrrocatechol(1.473 g, 13.393 mmol) in dry THF (10 mL). The reaction mixture wasallowed to warm to RT and stirred at RT for 30 min to yield catecholborane. To a solution of6-ethynyl-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1 g,4.464 mmol) in dry THF (20 mL) (in a two neck RBF equipped with refluxcondenser) was added dropwise catechol borane at 80° C. and the reactionmixture heated to reflux for 4 h. A hot solution of sodium hydroxide(500 mg) in EtOH (30 mL) and hydrogen peroxide (10 mL) were addeddropwise to the reaction mixture, which was heated to reflux for 5 min.The reaction mixture was quenched with ice water was and extracted withEtOAc (3×60 mL). The combined organic layer was washed with water (3×50mL), dried over anhydrous sodium sulfate and concentrated. The residuewas purified by silica gel column chromatography (0-4% methanol:DCM).

4-Bromopyridine (200 mg, 1.031 mmol) was placed under N₂ atmosphere anddissolved in THF (0.92 mL) at RT. Isopropylmagnesium chloride (1.03 mL,2.062 mmol) was added dropwise into the well stirred reaction mixtureand stirring continued at RT for 30 min (The Grignard reagent so formedis assumed to be 0.09 M solution). To a solution of2-(2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indol-6-yl)acetaldehyde(40 mg, 0.165 mmol) in dry THF (1 mL) was added dropwise thepyridylmagnesium bromide solution (˜0.09 M) (3.6 mL, 0.330 mmol) underanhydrous conditions and the reaction mixture stirred at RT for 30 min.The reaction mixture was quenched with a saturated solution of ammoniumchloride (10 mL) and extracted with EtOAc (2×30 mL). The combinedorganic layer was washed with water (1×20 mL), dried over anhydroussodium sulfate and concentrated. The residue was purified by reversephase chromatography to yield the title compound (2.43 mg). ¹H NMR(CD₃OD, Freebase) δ (ppm): 8.38 d (2H), 7.56 d (2H), 7.13 s (1H), 7.04 s(1H), 4.95 m (1H), 4.19 s (2H), 3.38 m (4H), 3.12 d (1H), 3.03 d (1H),2.9 s (3H), 2.44 s (3H).

Example 20 Preparation of Compound No. 44

To degassed mixture of6-bromo-2,3,4,5-tetrahydro-2,8-dimethyl-1H-pyrido[4,3-b]indole (1 g,3.60 mmol), copper(I)iodide (7 mg, 0.036 mmol),dichlorobis(triphenylphosphine)-palladium(II) (126 mg, 0.18 mmol) andtriethylamine (10 ml) was added ethynyl triisopropylsilane (786 mg, 4.32mmol) and the reaction mixture was stirred at 85° C. overnight. Theprogress of reaction was monitored by TLC and LCMS. The volatiles wereremoved under reduced pressure. The residue was diluted with water andextracted with EtOAc. The organic extracts were dried over anhydroussodium sulfate and concentrated to yield the desired compound, which wasused in the next reaction without further purification.

To an ice-cooled stirred solution of2,3,4,5-tetrahydro-6-(2-(triisopropylsilyl)ethynyl)-2,5,8-trimethyl-1H-pyrido[4,3-b]indole(1.6 g, 4.06 mmol) in dry THF (10 mL) was added dropwise a solution oftetrabutylammonium fluoride (1M solution in THF, 13 mL, 13 mmol). Thereaction mixture was allowed to warm to RT and stirred at RT for 15 min.Water was added into the reaction mixture, which was then filteredthrough Celite. The filtrate was extracted with EtOAc (2×25 mL). Theorganic layer was dried over anhydrous sodium sulfate and concentrated.The residue was recrystallized in hexane to yield the title compound(280 mg).

To an ice-cooled stirred solution of BH₃.DMS complex (0.6 mL, 6.302mmol) in dry THF (5 mL) was added dropwise a solution of pyrrocatechol(700 mg, 6.302 mmol) in dry THF (5 mL). The reaction mixture was allowedto warm to RT and stirred at RT for 30 min to yield catechol borane. Toa solution of6-ethynyl-2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indole (500mg, 2.101 mmol) in THF (20 mL), was added dropwise the catechol boranesolution at 80° C. and the reaction mixture heated to reflux for 4 h. Ahot solution of sodium hydroxide (250 mg) in ethanol (20 mL) andhydrogen peroxide (5 mL) was added dropwise to the reaction mixture,which was heated to reflux for 5 min. Ice water was added to thereaction mixture, which was then extracted with EtOAc (3×60 mL). Thecombined organic layer was washed with water (3×50 mL) and concentrated.The residue was purified by silica gel column chromatography (0-8%methanol:DCM).

To a degassed stirred solution of 4-bromopyridine.HCl (200 mg, 1.031mmol) in dry THF (0.92 mL) was added dropwise isopropylmagnesiumchloride (1.03 mL, 2.062 mmol) at RT for 30 min to yieldpyridylmagnesium bromide (which was assumed to be 0.09 M solution). To asolution of2-(2,3,4,5-tetrahydro-2,5,8-trimethyl-1H-pyrido[4,3-b]indol-6-yl)acetaldehyde(24 mg, 0.099 mmol) in dry THF (1 mL) was added dropwise thepyridylmagnesium bromide (˜0.09 M) (2.1 mL, 0.187 mmol) and the reactionmixture stirred at RT for 30 min. The reaction mixture was quenched witha saturated solution of ammonium chloride (5 mL), and extracted withEtOAc (2×25 mL). The combined organic extracts were washed with water(1×20 mL) and concentrated. The residue was purified by reverse phasechromatography. ¹H NMR (CD₃OD, Freebase) δ (ppm): 8.39 d (2H), 7.24 d(2H), 7.03 s (1H), 6.54 s (1H), 4.95 m (1H), 3.95 s (2H), 3.85 s (3H),3.21 m (4H), 2.89 m (2H), 2.76 s (3H), 2.27 s (3H).

Example 21 Preparation of N-Methyl and N-Ethyl9-Chloro-1,2,3,4,5,6-hexhydroazepino[4,3-b]indole

A mixture of 4-chloro-2-iodoaniline (0.5 g, 1.97 mmol),1,3-cyclohexanedione (0.22 g, 1.96 mmol) and p-toluenesulfonic acidmonohydrate (catalytic) in toluene (6 mL) were heated to reflux for 2 h.The reaction was cooled and EtOAc (50 mL) was added and the organicphase was washed with water (20 mL) and brine (20 mL), dried over sodiumsulfate, filtered and evaporated to give a brown solid, which waspurified by column chromatography [Silica, eluent: EtOAc:hexane to give3-(4-chloro-2-iodophenylamino)cyclohex-2-enone as a yellow solid (0.55g, 80%).

A mixture of 3-(4-chloro-2-iodo-phenylamino)-cyclohex-2-enone (0.5 g,1.44 mmol), cuprous iodide (27.4 mg, 0.14 mmol), L-proline (33.12 mg,0.29 mmol) and potassium hydroxide (0.32 g, 5.70 mmol) in DMSO (6 mL)were heated to 90° C. for 24 h. The reaction was cooled and poured intowater. The aqueous phase was extracted with EtOAc (3×50 mL). Thecombined organic phase was washed with brine (25 mL), dried overmagnesium sulfate, filtered and the solvent removed under reducedpressure to give a dark brown solid. This was recrystallized usingacetonitrile water to give a brown solid (0.17 g, 54%). mp 281-282° C.

A solution of 6-chloro-2,3-dihydro-1H-carbazol-4(9H)-one (500 mg, 2.27mmol), hydroxylamine hydrochloride (238 mg, 3.41 mmol) and NaOAc (280mg, 3.41 mmol) in EtOH:water (4.5:2 mL) was heated to reflux (125° C.)for 5 h. The reaction mixture was concentrated to dryness. Water wasadded to the residue and the solid filtered, dried under vacuum to yieldthe title compound.

6-Chloro-2,3-dihydro-1H-carbazol-4(9H)-one oxime (4.39 g, 18.71 mMol)and polyphosphoric acid (119 g) was heated together at 120° C. for 20min. After cooling to RT, ice-water mixture was added to hydrolyze themixture and stirred for 2 h. The mixture was filtered and washed withNH₄OH (40 ml) followed by water. The resultant solid was dissolved inMeOH and filtered. The methanolic solution was concentrated to yield 4.7g of crude as a brown solid. The crude product was purified by flashcolumn chromatography over silica-gel (230-400 mesh) using EtOAc/Hexanefollowed by MeOH/EtOAc, the product eluting at 2-10% MeOH/EA. Yield: 2.1g (47.8%).

To an ice-cooled stirred suspension of lithium aluminum hydride (486 mg,12.8 mmol) in dry THF (29 mL) was added dropwise a solution of9-chloro-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (380 mg, 1.62mmol) in dry THF (20 mL), and the reaction mixture heated to reflux for15 h (89° C.). The reaction mixture was cooled to RT, quenched withwater (3 mL), and 15% NaOH solution (6 mL) and water (9 mL), and thendiluted with THF. The reaction mixture was filtered through Celite andthe filtrate concentrated under reduced pressure to yield the titlecompound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360mg, 1.6 mmol) in THF (1 mL) was added dropwise to ethyl formate (1 mL).The reaction mixture was stirred at RT for 30 min, followed by heatingto reflux for 14 h. The solvent was removed under reduced pressure toyield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (360mg, 1.6 mmol) was stirred in acetic anhydride for 12 h. The solvent wasremoved under reduced pressure to yield the title compound.

A solution of 9-chloro-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (12.3g, 55.9 mmol) in ethyl formate (369 mL) was stirred at 55° C. for 2 h.The progress of reaction was monitored by TLC. The reaction mixture wasconcentrated under reduced pressure and the crude product (13.5 g) wasused for the next step without purification. To a stirred suspension oflithium aluminum hydride (4.13 g, 108.8 mmol) in dry THF (405 mL) wasadded portionwise9-chloro-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (13.5g) and the mixture heated to reflux for 2 h. The progress of reactionwas monitored by TLC. The reaction was quenched with saturated aqueoussodium sulfate solution at 0° C., and the mixture filtered. The filtratewas dried over anhydrous sodium sulfate and evaporated to dryness. Theresidue was washed with diethyl ether to yield the title compound (9.7g). ¹H NMR (DMSO) δ (ppm): 11.02 (s, 1H, D₂O exchangeable), 7.45 (s,1H), 7.25-7.22 (d, 1H), 6.98-6.95 (d, 1H), 3.72 (s, 2H), 2.90-2.80 (m,4H), 2.30 (s, 3H), 1.82-1.77 (m, 2H).

To an ice-cooled stirred suspension of lithium aluminum hydride (390 mg,10.09 mmol) in 1,4-dioxane (15 mL) was added portionwise1-(9-chloro-4,5-dihydroazepino[4,3-b]indol-2(1H,3H,6H)-yl)ethanone (300mg, 1.14 mmol), and the reaction mixture heated to reflux for 6 h. Thereaction mixture was quenched with water (1 mL), 15% aq. NaOH solution(3 mL) and water (3 mL), and extracted with warm EtOAc (3×50 mL). Thecombined organic extract was concentrated and the residue purified bysilica gel (230-400 mesh) flash column chromatography (100% EtOAc) toyield the title compound (115 mg).

Example 22 Preparation of2,9-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole

To a solution of p-tolylhydrazine hydrochloride (7.5 g, 47.2 mmol) in1,4-dioxane:conc. H₂SO₄ (225:16.5 mL) was added cyclohexane-1,3-dione(4.42 g, 39.4 mmol), and the mixture heated to reflux for 16 h (85-90°C.). The reaction mixture was cooled to RT, basified with 15% aqueousKOH (pH 10) and extracted with EtOAc. The organic layer was washed twicewith brine, dried over anhydrous sodium sulfate and concentrated underreduced pressure to yield the title compound (7.7 g, crude).

A solution of 2,3-dihydro-6-methyl-1H-carbazol-4(9H)-one (5.8 g, 19.1mmol), hydroxylamine hydrochloride (3.0 g, 43.6 mmol) and NaOAc (3.58 g,43.6 mmol) in EtOH:water (58:25.3 mL) was heated to reflux (125° C.) for5 h. The reaction mixture was concentrated to dryness. Water was addedto the residue and the solid filtered, dried under vacuum to yield titlecompound.

To a preheated (105° C.) solution of polyphosphoric acid (225 g) wasadded powdered 6-methyl-2,3-dihydro-1H-carbazol-4(9H)-one oxime (10 g)under nitrogen and heating continued for 15 min. The reaction mixturewas cooled and to it was added crushed ice water. The crystallized solidobtained was collected by filtration. The solid was washed with waterand then by dilute ammonium hydroxide, then dried under vacuum to obtainthe desired product (8 g, crude product).

Lithium aluminum hydride (3 g, 78.95 mmol) was placed in 1,4-dioxane(100 mL) under inert atmosphere and9-methyl-2,3,4,5-tetrahydroazepino[4,3-b]indol-1(6H)-one (3 g, 14.018mmol) was added, and the mixture heated to reflux for 15 h. The reactionwas monitored by TLC. The reaction was quenched with saturated aqueoussodium sulfate at 0° C., and the reaction mixture filtered. The filtratewas dried over anhydrous sodium sulfate and evaporated to dryness toafford solid, which was washed with water followed by EtOAc, and driedto afford 1.25 g of the title compound.

9-Methyl-1,2,3,4,5,6-hexahydroazepino[4,3-b]indole (0.25 g, 1.25 mmol)was taken in ethyl formate (18 mL, 227 mmol) and stirred at 55° C. for 3h. The reaction was monitored by TLC. The reaction mixture wasevaporated under reduced pressure and used for the next step withoutpurification (0.2 g).

To a stirred suspension of lithium aluminum hydride (2 g, 52.63 mmol) indry THF (150 mL) was added portionwise9-methyl-3,4,5,6-tetrahydroazepino[4,3-b]indole-2(1H)-carbaldehyde (5.9g, 25.87 mmol) and the reaction mixture stirred at 55° C. for 2 h. Theprogress of reaction was monitored by TLC. The reaction mixture wasquenched with saturated sodium aqueous sulfate solution at 0° C. andthen filtered. The filtrate was dried over anhydrous sodium sulfate andevaporated to dryness to afford the title compound (5.2 g). ¹H NMR(DMSO) δ (ppm): 7.12-7.05 (m, 2H), 6.80-6.6.76 (d, 1H), 3.65 (s, 2H),2.90-2.80 (m, 4H), 2.34 (s, 3H), 2.26 (s, 3H), 1.80-1.72 (m, 2H).

Example B1 Determination of the Ability of Compounds of the Invention toBind a Histamine Receptor Histamine H₁

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H1 receptor expressed inChinese hamster ovary (CHO) K1 cells (De Backer, M. et al, Biochem.Biophys. Res. Comm. 197(3):1601, 1993) in a modified Tris-HCl buffer (50mM Tris-HCl, pH 7.4, 2 mM MgCl₂, 100 mM NaCl, 250 mM Sucrose) was used.Compounds of the invention were incubated with 1.2 nM [³H]Pyrilamine for180 min at 25° C. Non-specific binding was estimated in the presence of1 μM Pyrilamine. Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]Pyrilamine specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 2.

Histamine H₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H2 receptor expressed inChinese hamster ovary (CHO) K1 cells (Ruat, M., Proc. Natl. Acad. Sci.USA. 87(5):1658, 1990) in a 50 mM Phosphate buffer, pH 7.4 is used.Compounds of the invention are incubated with 0.1 nM[¹²⁵I]Aminopotentidine for 120 min at 25° C. Non-specific binding isestimated in the presence of 3 μM Tiotidine. Receptor proteins arefiltered and washed, the filters are then counted to determine[¹²⁵I]Aminopotentidine specifically bound. Compounds are screened at 1μM or lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Histamine H₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant histamine H₃ receptor expressed inChinese hamster ovary (CHO) K1 cells (Krueger, K. et al. J. Pharmacol.Exp. Ther. 314(1):271, 2005); Yanai, K. et al, Jpn. J. Pharmacol.65(2):107, 1994; Zhu, Y. et al, Mol. Pharmacol. 59(3):434, 2001) in amodified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.1% BSA)is used. Compounds of invention are incubated with 0.4 nM[³H]Nα-Methylhistamine for 12 min at 25° C. Non-specific binding isestimated in the presence of 1 μM R(−)-α-Methylhistamine. Receptorproteins are filtered and washed, the filters are then counted todetermine [³H] R(−)-α-Methylhistamine specifically bound. Compounds arescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention are tested in this biochemical assay and percent inhibition ofspecific binding is determined.

Example B2 Determination of the Ability of Compounds of the Invention toBind a Imidazoline I₂ Receptor Central Imidazoline I₂

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat central imidazoline I₂ receptor obtained from WistarRat cerebral cortex (Brown, C. et al, Br. J. Pharmacol. 99:803, 1990) ina modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA)is used. Compounds of the invention are incubated with 2 nM [³H]Idazoxanfor 30 min at 25° C. Non-specific binding is estimated in the presenceof 1 μM Idazoxan. Receptor proteins are filtered and washed, the filtersare then counted to determine [³H]Idazoxan specifically bound. Compoundsare screened at 1 μM or lower, using 1% DMSO as vehicle. Compounds ofthe invention are tested in this biochemical assay and percentinhibition of specific binding is determined.

TABLE 2 Binding data (Percentage inhibition) Compound No. Histamine H₁(1 μM) 1 6 2 58 3 14 4 15 5 17 6 16 Histamine H₁ (0.1 μM) 7 6 8 −3 9 010 5 11 −3 12 −14 13 28 14 25 15 2 16 9 17 39 18 12

Example B3 Determination of the Ability of Compounds of the Invention toBind an Adrenergic Receptor Adrenergic α_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1A) receptor obtained from Wistar Ratsubmaxillary glands (Michel, A. et al, Br. J. Pharmacol. 98:883, 1989)in a modified Tris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mMEDTA) was used. Compounds of the invention were incubated with 0.25 nM[³H]Prazosin for 60 min at 25° C. Non-specific binding was estimated inthe presence of 10 μM phentolamine. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Prazosinspecifically bound. Compounds of the invention were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 3.

Adrenergic α_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, rat adrenergic α_(1B) receptor obtained from Wistar Ratliver (Garcia-S'ainz, J. et al, Biochem. Biophys. Res. Commun. 186:760,1992; Michel, A. et al, Br. J. Pharmacol. 98:883, 1989) in a modifiedTris-HCl buffer (50 mM Tris-HCl buffer, pH 7.4, 0.5 mM EDTA) was used.Compounds of the invention were incubated with 0.25 nM [³H]Prazosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 3.

Adrenergic α_(1D)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(1D) receptor expressed inhuman embryonic kidney (HEK-293) cells (Kenny, B. et al, Br. J.Pharmacol. 115(6):981, 1995) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of invention were incubated with 0.6 nM [³H]Prazosin for60 min at 25° C. Non-specific binding was estimated in the presence of10 μM phentolamine. Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]Prazosin specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 3.

Adrenergic α_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2A) receptor expressed ininsect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of invention were incubated with 1nM [³H]MK-912 for 60 min at 25° C. MK-912 is(2S-trans)-1,3,4,5′,6,6′,7,12b-octahydro-1′,3′-dimethyl-spiro[2H-benzofuro[2,3-a]quinolizine-2,4′(1′H)-pyrimidin]-2′(3′H)-onehydrochloride Non-specific binding was estimated in the presence of 10μM WB-4101 (2-(2,6-Dimethoxyphenoxyethyl)aminomethyl-1,4-benzodioxanehydrochloride). Receptor proteins were filtered and washed, the filterswere then counted to determine [³H]MK-912 specifically bound. Compoundswere screened at 1 μM or lower, using 1% DMSO as vehicle. Biochemicalassay results are presented as the percent inhibition of specificbinding in Table 3.

Adrenergic

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2B) receptor expressed inChinese hamster ovary (CHO) K1 cells (Uhlen, S. et al, Eur. J.Pharmacol. 343(1):93, 1998) in a modified Tris-HCl buffer (50 mMTris-HCl, pH 7.4, 12.5 mM MgCl₂, 1 mM EDTA, 0.2% BSA) was used.Compounds of the invention were incubated with 2.5 nM [³H]Rauwolscinefor 60 min at 25° C. Non-specific binding was estimated in the presenceof 10 μM Prazosin. Receptor proteins were filtered and washed, thefilters were then counted to determine

[³H]Rauwolscine specifically bound. Compounds were screened at 1 μM orlower, using 1% DMSO as vehicle. Biochemical assay results are presentedas the percent inhibition of specific binding in Table 3.

Adrenergic α_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant adrenergic α_(2C) receptor expressed ininsect Sf9 cells (Uhlen, S. et al, J. Pharmacol. Exp. Ther. 271:1558,1994) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 12.5 mMMgCl₂, 2 mM EDTA) was used. Compounds of the invention were incubatedwith 1 nM [³H]MK-912 for 60 min at 25° C. Non-specific binding wasestimated in the presence of 10 μM WB-4101. Receptor proteins werefiltered and washed, the filters were then counted to determine[³H]MK-912 specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 3.

Example B4 Determination of the Ability of Compounds of the Invention toBind a Dopamine Receptor Dopamine D_(2L)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant dopamine D_(2L) receptor expressed inChinese hamster ovary (CHO) cells (Grandy, D. et al, Proc. Natl. Acad.Sci. USA. 86:9762, 1989; Hayes, G. et al, Mol. Endocrinol. 6:920, 1992)in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1.4 mM AscorbicAcid, 0.001% BSA, 150 mM NaCl) was used. Compounds of the invention wereincubated with 0.16 nM [³H]Spiperonefor 120 min at 25° C. Non-specificbinding was estimated in the presence of 10 μM Haloperidol. Receptorproteins were filtered and washed, the filters were then counted todetermine [³H]Spiperone specifically bound. Compounds were screened at 1μM or lower, using 1% DMSO as vehicle. Biochemical assay results arepresented as the percent inhibition of specific binding in Table 3.

TABLE 3 Percentage inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Dopamine CompoundAdrenergic (0.1 μM) (1 μM) No. α_(1A) α_(1B) α_(1D) α_(2A) α_(2B) α_(2C)D_(2L) 1 — — — — — — 21 2 — — — — — — 6 3 — — — — — — 19 4 — — — — — — 55 — — — — — — 10 6 — — — — — — 7 7 1 2 4 10 −9 8 5 8 −5 −3 3 20 −1 7 −19 4 −9 −1 0 −7 1 7 10 6 11 26 23 8 36 70 11 −14 −1 −1 4 14 12 28 12 −122 38 −4 6 3 14 13 2 −9 8 −12 5 2 15 14 −16 0 −9 12 −3 1 14 15 3 0 5 2021 −14 3 16 −1 1 −2 31 17 5 −1 17 −2 9 −5 14 21 3 1 18 14 30 34 6 38 0 7

Example B5 Determination of the Ability of Compounds of the Invention toBind a Serotonin Receptor Serotonin (5-Hydroxytryptamine) 5-HT_(1A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(1A) receptor expressed in Chinese hamster ovary (CHO) K1 cells(Martin, G. et al, Neuropharmacol. 33:261, 1994; May J. et al, J.Pharmacol. Exp. Ther. 306(1):301, 2003) in a modified Tris-HCl buffer(50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 0.5 mM EDTA, 10 mM MgSO₄)is used. Compounds of invention are incubated with 1.5 nM [³H]8-OH-DPATfor 60 min at 25° C. Non-specific binding is estimated in the presenceof 10 μM Metergoline. Receptor proteins are filtered and washed, thefilters are then counted to determine [³H] 8-OH-DPAT specifically bound.Compounds are screened at 1 μM or lower, using 1% DMSO as vehicle.Compounds of the invention are tested in this biochemical assay andpercent inhibition of specific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(1B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT_(1B) receptor fromWistar Rat cerebral cortex (Hoyer et al, Eur. J. Pharmacol. 118:1, 1985;Pazos et al, Eur. J. Pharmacol. 106:531, 1985) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 154 mM NaCl, 10 μM Pargyline, 30 μMIsoprenaline) is used. Compounds of invention are incubated with 10 μM[¹²⁵I]Cyanopindolol for 90 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are counted to determine[¹²⁵I]Cyanopindolol specifically bound. Compounds are screened at 1 μMor lower, using 1% DMSO as vehicle. Compounds of the invention aretested in this biochemical assay and percent inhibition of specificbinding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2A) receptor expressed in Chinese hamster ovary (CHO) K1 cells(Bonhaus, D. et al, Br. J. Pharmacol. 115:622, 1995; Saucier, C. et al,J. Neurochem. 68:1998, 1997) in a 50 mM Tris-HCl buffer, pH 7.4, wasused. Compounds of the invention were incubated with 0.5 nM[³H]Ketanserin for 60 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Ketanserinspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT_(2B)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2B) receptor expressed in Chinese hamster ovary (CHO) K1 cells(Bonhaus, D. et al, Br. J. Pharmacol. 115:622, 1995) in a modifiedTris-HCl buffer (50 mM Tris-HCl, pH 7.4, 4 mM CaCl₂, 0.1% Ascorbic Acid)is used. Compounds of invention are incubated with 1.2 nM [³H]Lysergicacid diethylamide (LSD) for 60 min at 37° C. Non-specific binding isestimated in the presence of 10 μM Serotonin (5-HT). Receptor proteinsare filtered and washed, the filters are then counted to determine[³H]LSD specifically bound. Compounds are screened at 1 μM or lower,using 1% DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT_(2C)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(2C) receptor expressed in Chinese hamster ovary (CHO) K1 cells(Wolf, W. et al, J. Neurochem. 69:1449, 1997) in a modified Tris-HClbuffer (50 mM Tris-HCl, pH 7.4, 0.1% Ascorbic Acid, 10 μM Pargyline) wasused. Compounds of the invention were incubated with 1 nM[³H]Mesulergine for 60 min at 25° C. Non-specific binding was estimatedin the presence of 1 μM Mianserin. Receptor proteins were filtered andwashed, the filters were then counted to determine [³H]Mesulerginespecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₃

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₃receptor expressed in human embryonic kidney (HEK-293) cells (Miller, K.et al, Synapse 11:58, 1992; Boess, F. et al, Neuropharmacology 36:637,1997) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4, 1 mM EDTA,5 mM MgCl₂) is used. Compounds of invention are incubated with 0.69 nM[³H]GR-65630 for 60 min at 25° C. Non-specific binding is estimated inthe presence of 10 μM MDL-72222. Receptor proteins are filtered andwashed, the filters are then counted to determine [³H]GR-65630specifically bound. Compounds are screened at 1 μM or lower, using 1%DMSO as vehicle. Compounds of the invention are tested in thisbiochemical assay and percent inhibition of specific binding isdetermined.

Serotonin (5-Hydroxytryptamine) 5-HT₄

To evaluate in radioligand binding assays the activity of compounds ofthe invention, serotonin (5-Hydroxytryptamine) 5-HT₄ receptor fromDuncan Hartley derived Guinea pig striatum (Grossman, C. et al, Br. J.Pharmacol. 109:618, 1993) in a 50 mM Tris-HCl, pH 7.4, is used.Compounds of invention are incubated with 0.7 nM [³H]GR-113808 for 30min at 25° C. Non-specific binding is estimated in the presence of 30 μMSerotonin (5-HT). Receptor proteins are filtered and washed, the filtersare counted to determine [³H]GR-113808 specifically bound. Compounds arescreened at 1 μM or lower, using 1% DMSO as vehicle. Compounds of theinvention are tested in this biochemical assay and percent inhibition ofspecific binding is determined.

Serotonin (5-Hydroxytryptamine) 5-HT_(5A)

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine)5-HT_(5A) receptor expressed in Chinese hamster ovary (CHO) K1 cells(Rees, S. et al, FEBS Lett. 355:242, 1994) in a modified Tris-HCl buffer(50 mM Tris-HCl, pH 7.4, 10 mM MgCl₂, 0.5 mM EDTA) was used. Compoundsof the invention were incubated with 1.7 nM [³H]Lysergic aciddiethylamide (LSD) for 60 min at 37° C. Non-specific binding wasestimated in the presence of 100 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were counted to determine [³H]LSDspecifically bound. Compounds were screened at 1 μM or lower, using 1%DMSO as vehicle. Biochemical assay results are presented as the percentinhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₆

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₆receptor expressed in human HeLa cells (Monsma, F. Jr. et al, Mol.Pharmacol. 43:320, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl,pH 7.4, 150 mM NaCl, 2 mM Ascorbic Acid, 0.001% BSA) was used. Compoundsof the invention were incubated with 1.5 nM [3H]Lysergic aciddiethylamide (LSD) for 120 min at 37° C. Non-specific binding wasestimated in the presence of 5 μM Serotonin (5-HT). Receptor proteinswere filtered and washed, the filters were then counted to determine[3H]LSD specifically bound. Compounds were screened at 1 μM or lower,using 1% DMSO as vehicle. Biochemical assay results are presented as thepercent inhibition of specific binding in Table 4.

Serotonin (5-Hydroxytryptamine) 5-HT₇

To evaluate in radioligand binding assays the activity of compounds ofthe invention, human recombinant serotonin (5-Hydroxytryptamine) 5-HT₇receptor expressed in Chinese hamster ovary (CHO) cells (Roth, B. et al,J. Pharmacol. Exp. Ther. 268:1403, 1994; Shen, Y. et al, J. Biol. Chem.268:18200, 1993) in a modified Tris-HCl buffer (50 mM Tris-HCl, pH 7.4,10 mM MgCl₂, 0.5 mM EDTA) was used. Compounds of invention wereincubated with 5.5 nM [³H] Lysergic acid diethylamide (LSD) for 2 h at25° C. Non-specific binding was estimated in the presence of 10 μMSerotonin (5-HT). Receptor proteins were filtered and washed, thefilters were then counted to determine [³H]LSD specifically bound.Compounds were screened at 1 μM or lower, using 1% DMSO as vehicle.Biochemical assay results are presented as the percent inhibition ofspecific binding in Table 4.

TABLE 4 Percentage inhibition of ligand binding to aminergic G protein-coupled receptors by compounds of the invention: Serotonin (0.1 μM)Compound No. 5-HT_(2A) 5-HT_(2C) 5-HT_(5A) 5-HT₆ 5-HT₇ 1 73 55 — 44 9 26 36 — 4 17 3 40 41 — 13 14 4 −7 7 — 2 −10 5 54 45 — 30 45 6 41 55 — 2443 7 6 36 −4 10 12 8 27 4 −14 15 6 9 5 9 6 −2 26 10 37 55 1 18 14 11 13−11 −19 −6 −17 12 23 3 −21 −3 5 13 13 −11 15 2 16 14 −7 1 −7 10 13 15 128 11 11 36 16 21 20 −2 14 35 17 24 19 15 5 23 18 80 27 17 6 8

Example B6 Determination of Serotonin (5-Hydroxytryptamine) 5-HT_(2A) or5-HT₇ Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant serotonin 5-HT_(2A)receptor expressed in human embryonic kidney (HEK-293) cells (Jerman etal., Eur. J. Pharmacol. 414:23-30, 2001) or human recombinant serotonin5-HT₇ receptor expressed in CHO cells (Adham et al, J. Pharmacol. Exp.Ther. 287:508-514, 1998) is used. Cells are suspended in DMEM buffer,and distributed in microplates. For the 5-HT_(2A) assay, a cytoplasmiccalcium fluorescent indicator which varies proportionally to the freecytosolic Ca²⁺ ion concentration is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4), added into each well andequilibrated with the cells for 30 min at 37° C. followed by 30 min at22° C. For the 5-HT₇ assay, the reaction product is cAMP, detected byHTRF.

To measure 5-HT_(2A) agonist effects, compounds of the invention,reference agonist or HBSS buffer (basal control) is added to the cellsand changes in fluorescence intensity are measured using a microplatereader. For stimulated control measurements, 5-HT at 100 nM is added inseparate assay wells. The results are expressed as a percent of thecontrol response to 100 nM 5-HT. The standard reference agonist is 5-HT,which is tested in each experiment at several concentrations to generatea concentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 3 nM 5-HT (5-HT_(2A)), 100 nM 5-HT (5-HT₇) or HBSS buffer(basal control) prior the fluorescence measurements. The results areexpressed as a percent inhibition of the control response to 3 nM 5-HT.The standard reference antagonist is ketanserin (5-HT_(2A)) ormesulergine (5-HT₇), which is tested in each experiment at severalconcentrations to generate a concentration-response curve from which itsIC₅₀ value is calculated. Compounds are screened at 3 μM or lower, usingDMSO as vehicle.

Example B7 Determination of Serotonin (5-Hydroxytryptamine) 5-HT₆Agonist/Antagonist Activity of Compounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant 5-HT₆ receptor istransfected in CHO cells (Kohen, R. et al, J. Neurochem. 66:47, 1996)and the activity of compounds of the invention is determined bymeasuring their effects on cAMP production using the Homogeneous TimeResolved Fluorescence (HTRF) detection method. Cells are suspended inHBSS buffer complemented with HEPES 20 mM (pH 7.4) and 500 μM IBMX, andthen distributed in microplates and incubated for 45 min at 37° C. inthe absence (control) or presence of compounds of the invention or thereference agonist or antagonist.

For agonist determinations, stimulated control measurement, separateassay wells contain 10 μM 5-HT. Following incubation, the cells arelysed and the fluorescence acceptor (D2-labeled cAMP) and fluorescencedonor (anti-cAMP antibody labeled with europium cryptate) are added.After 60 min at room temperature, the fluorescence transfer is measuredat lex=337 nm and lem=620 and 665 nm using a microplate reader. The cAMPconcentration is determined by dividing the signal measured at 665 nm bythat measured at 620 nm (ratio).

The results are expressed as a percent of the control response to 10 μM5-HT. The standard reference agonist is 5-HT, which is tested in eachexperiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

For antagonist determinations, the reference agonist 5-HT is added at afinal concentration of 100 nM. For basal control measurements, separateassay wells do not contain 5-HT. Following 45 min incubation at 37° C.,the cells are lysed and the fluorescence acceptor (D₂-labeled cAMP) andfluorescence donor (anti-cAMP antibody labeled with europium cryptate)are added.

After 60 min at room temperature, the fluorescence transfer is measuredas mentioned above. The results are expressed as a percent inhibition ofthe control response to 100 nM 5-HT. The standard reference antagonistis methiothepin.

Example B8 Determination of Dopamine D_(2L) Antagonist Activity ofCompounds

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D_(2L)receptor stably expressed in Chinese hamster ovary (CHO) cells(Senogles, S. et al, J. Biol. Chem. 265(8):4507, 1990) is used.Compounds of the invention are pre-incubated with the membranes (0.1mg/mL) and 10 mM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4, 100mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 min and ScintillationProximity Assay (SPA) beads are added for another 60 min at 30° C. Thereaction is initiated by 0.3 nM [³⁵S]GTPγS for an additional 15 minincubation period. Increase of [³⁵S]GTPγS binding by 50% or more (350%)relative to the 1 mM dopamine response by compounds of the inventionindicates possible dopamine D_(2L), receptor agonist's activity.Inhibition of a 10 μM dopamine-induced increase of [³⁵S]GTPγS bindingresponse by 50% or more (350%) by compounds of the invention indicatesreceptor antagonist activity. Compounds are screened at 3 μM or lower,using 0.4% DMSO as vehicle. Assay results are presented as the percentresponse of specific binding.

Example B9 Determination of Dopamine D_(2S) Antagonist Activity ofCompounds of the Invention

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant dopamine D₂₅ receptorstably expressed in Chinese hamster ovary (CHO) cells (Gilliland, S. etal, Naunyn-Schmiedeberg's Archives of Pharmacology 361:498, 2000) isused. Compounds of the invention are pre-incubated with the membranes(0.05 mg/mL) and 3 μM GDP in modified HEPES buffer (20 mM HEPES, pH 7.4,100 mM NaCl, 10 mM MgCl₂, 1 mM DTT, 1 mM EDTA) for 20 min andScintillation Proximity Assay (SPA) beads are then added for another 60min at 30° C. The reaction is initiated by 0.3 nM [³⁵S]GTPγS for anadditional 30 min incubation period. Increase of [³⁵S]GTPγS binding by50 percent or more (350%) relative to the 100 μM dopamine response bycompounds of the invention indicates possible dopamine D₂₅ receptoragonist's activity. Inhibition of a 3 μM dopamine-induced increase of[³⁵S]GTPγS binding response by 50 percent or more (350%) by compounds ofthe invention indicates receptor antagonist activity. Compounds arescreened at 3 μM or lower, using 0.4% DMSO as vehicle. Assay results arepresented as the percent response of specific binding.

Example B10 Determination for Agonist or Antagonist Activity ofCompounds of the Invention in a Histamine H₁ Functional Assay

To determine for agonist or antagonist activity of compounds of theinvention in functional assays, human recombinant Histamine H₁ receptorexpressed in human embryonic kidney (HEK-293) cells (Miller, T. et al,J. Biomol. Screen. 4: 249-258, 1999) is used. Cells are suspended inDMEM buffer, and then distributed in microplates. A cytoplasmic calciumfluorescent indicator—which varies proportionally to the free cytosolicCa²⁺ ion concentration is mixed with probenecid in HBSS buffercomplemented with 20 mM HEPES (pH 7.4) and is then added into each welland equilibrated with the cells for 30 min at 37° C. and then foranother 30 min at 22° C. To measure agonist effects, compounds of theinvention, reference agonist or HBSS buffer (basal control) are added tothe cells and changes in fluorescence intensity are measured using amicroplate reader. For stimulated control measurements, histamine at 10μM is added in separate assay wells.

The results are expressed as a percent of the control response to 10 μMhistamine. The standard reference agonist is histamine, which is testedin each experiment at several concentrations to generate aconcentration-response curve from which its EC₅₀ value is calculated.

To measure antagonist effects, the addition of the compounds of theinvention, reference antagonist or HBSS buffer is followed by theaddition of 300 nM histamine or HBSS buffer (basal control) prior thefluorescence measurements. The results are expressed as percentinhibition of the control response to 300 nM histamine. The standardreference antagonist is ketanserin, which is tested in each experimentat several concentrations to generate a concentration-response curvefrom which its IC₅₀ value is calculated. Compounds are screened at 3 μMor lower, using DMSO as vehicle.

Example B11 Determination of Binding Activity of Compounds of theInvention at the 5-HT_(1B) Receptor with a Radioligand BindingCompetition Assay

To determine the binding activity at the human recombinant serotonin5-HT_(1B) receptor of compounds of the invention, CHO-K1 cell lineexpressing the human 5-HT_(1B) recombinant receptor is amplified toprepare membranes used for the radioligand binding assay throughout thestudy. Radioligand binding competition on 5-HT_(1B) is performed byadding successively in the wells of a 96 well plate (Master Block,Greiner, 786201) 50 μL of test compounds or reference ligand (5-HT,Sigma, H-9523) at increasing concentrations (diluted in binding buffer:50 mM Tris pH 7.4, 12.5 mM MgCl₂, 0.1% Ascorbic Acid, 1 mM EDTA, pH7.4), 25 μL [³H]5-CT (Amersham, TRK1038, diluted in assay buffer for afinal concentration of 0.6 nM) and 25 μL 5-HT1B membrane extracts (7μg/well). Non specific binding is determined by co-incubation with200-fold excess of 5-HT. The plate is incubated 60 min at 25° C. in awater bath and then filtered over GF/B filters (Perkin Elmer, 6005177,presoaked in 0.5% PEI for 2 h at room temperature) with a Filtrationunit (Perkin Elmer). The filters are washed 3× with 0.5 mL of ice-coldwashing buffer (50 mM Tris pH 7.4), 50 μL Microscint 20 (Packard) isadded and the plate is incubated 15 min on an orbital shaker and thencounted with a TopCount™ for 1 min/well.

On each day of experimentation and prior to the testing of compounds,the reference compound is tested at several concentrations in duplicate(n=2) to obtain a dose-response curve and an estimated IC₅₀ value. Thereference value thus obtained for the test is compared to a historicalvalue obtained from the same receptor and used to validate theexperimental session. A session is considered as valid only if thereference value is found to be within a 0.5 logs interval from thehistorical value. For replicate determinations, the maximum variabilitytolerated in the test is of +/−20% around the average of the replicates.

Compounds are tested for binding activity in the radioligand bindingcompetition assay on human 5-HT_(1B) receptor, at one concentration 5μM, in duplicate. Dose-response data from test compounds are analyzedwith XLfit (IDBS) software using nonlinear regression applied to asigmoidal dose-response model.

Example B12 Functional Activity on Recombinant Dopamine D_(2L) andSerotonin 5-HT_(2A) Receptors Using Aequorin, cAMP and GTPγS FunctionalAssays

To study the functional activity of compounds of the invention on thehuman recombinant dopamine D_(2L) with Aequorin, GTPγS and cAMPfunctional assays and on the human recombinant serotonin 5-HT_(2A)receptor with Aequorin, CHO-K1 cell lines expressing D_(2L) or 5-HT_(2A)recombinant receptor, mitochondrial apoaequorin and Gα16 are used forthe Aequorin assay. CHO-K1 cell line expressing the recombinant D_(2L)receptor is used for the cAMP assay and is amplified to preparemembranes used for the GTPγS assay.

Aequorin Assay Procedure: Aequorin dopamine D_(2L) (FAST-0101A) orserotonin 5-HT_(2A) (FAST-0505A) cells, grown 18 h prior to the test inmedia without antibiotics, are detached by gentle flushing with PBS-EDTA(5 mM EDTA), recovered by centrifugation and resuspended in “assaybuffer” (DMEM/HAM's F12 with HEPES, without phenol red+0.1% BSA proteasefree). Cells are incubated at RT for at least 4 h with Coelenterazine h(Molecular Probes). Dose response curves with reference compounds areperformed before testing the compounds of the invention. D_(2L)reference agonist and antagonist are quinpirol (Tocris, 1061) andhaloperidol (Tocris, 0931), respectively. 5-HT_(2A) reference agonistand antagonist are α-methyl-5-HT (Sigma, M-110) and ketanserin (Tocris,908), respectively. For agonist testing, 50 μL of cell suspension areinjected on 50 μL of test compound or reference agonist plated in a96-well plate. The resulting emission of light is recorded using theHamamatsu Functional Drug Screening System 6000 (FDSS 6000). Followingan incubation of 15 min after the first injection, 100 μL of referenceagonist at a concentration corresponding to its EC₈₀ is injected on the100 μL of the mixture of cell suspension and test compound, forantagonist testing. The resulting emission of light is recorded usingthe same luminometer as for agonist testing. To standardize the emissionof recorded light (determination of the “100% signal”) across plates andacross different experiments, some of the wells contain 100 μM digitoninor a saturating concentration of ATP (20 μM). Plates also contain thereference agonist at a concentration equivalent to the EC₁₀₀ and EC₈₀obtained during the test validation. Compounds are tested for agonist &antagonist activity at the human dopamine D_(2L), receptor (FAST-0101A)and serotonin 5-HT_(2A) receptor (FAST-0505A) at the following nanomolarconcentrations, in duplicate: Agonist (nM): 10, 30, 100, 300, 1000,3000, 10000, 30000; Antagonist (nM): 5, 15, 50, 150, 500, 1500, 5000,15000.

cAMP Assay Procedure: D_(2L), CHO-K1 cells (FAST-0101C), grown tomid-log phase in culture media without antibiotics, are detached withPBS-EDTA (5 mM EDTA), centrifuged and resuspended in assay buffer (KRH,1 mM IBMX) at a concentration of 2.1×10⁵ cells/mL. The test is performedin 96 well plates. For agonist testing, 12 μL of cells (2,500cells/well) are mixed with 6 μL of increasing concentrations of testcompound or reference agonist and 6 μL of Forskolin 10 μM finalconcentration (Calbiochem, cat n° 344270). For antagonist testing, 12 μLof cells (2,500 cells/well) are mixed with 6 μL of test compound orreference antagonist at increasing concentrations. After incubation of10 min at room temperature, 6 μL of a mix of Forskolin 10 μM finalconcentration and the reference agonist at a final concentrationcorresponding to the EC₈₀ are added. The plates are then incubated for30 min at room temperature. During the incubation, the anti-cAMPcryptate antibody (K) and the cAMP-D2 (D2) are prepared according to themanufacturer specifications (HTRF kit from Cis-Bio International (cat no62AM2PEB). 12 μL of cAMP-D₂ solution followed by 12 μL of K solution areadded to each well. The plate is then covered by a top-seal andincubated for at least 1 h at room temperature. The plate is then readon the Rubystar and data are analyzed by non-linear regression using asingle site model. Compounds are tested for antagonist activity at thehuman dopamine D_(2L) receptor (FAST-0101C) at the following nanomolarconcentrations, in duplicate: Antagonist (nM): 5, 15, 50, 150, 500,1500, 5000, 15000.

GTPγS Assay Procedure: Assay buffer [20 mM HEPES pH 7.4; 100 mM NaCl, 10μg/mL saponin, 30 mM MgCl₂]; Membranes [Recombinant CHO-K1-D_(2L)membrane extracts thawed on ice and diluted in assay buffer to give 1mg/mL (10 μg/10 μL) and kept on ice]; GDP [diluted in assay buffer togive 3 μM final concentration]; Beads [PVT-WGA (Amersham, RPNQ0001),diluted in assay buffer at 25 mg/mL (0.25 mg/10 μL)]; GTPγ³⁵S[(PerkinElmer NEG030X), diluted in assay buffer to give 0.1 nM finalconcentration]; Ligand [Quinpirol (Tocris, 1061) as reference agonistand haloperidol (Tocris, 0931) as reference antagonist, diluted in assaybuffer]. Membranes are mixed with GDP (volume:volume) and incubated forat least 15 min on ice. In parallel, GTPγ[³⁵S] is mixed with the beads(volume:volume) just before starting the reaction. For agonist testing,the following reagents are successively added in the wells of anOptiplate (Perkin Elmer): 50 μL of test or reference ligand, 20 μL ofthe membranes:GDP mix, 10 μL of assay buffer and 20 μL of theGTPγ[³⁵S]:beads mix. For antagonist testing, the following reagents aresuccessively added in the wells of an Optiplate (Perkin Elmer): 50 μL oftest or reference ligand, 20 μL of the membranes:GDP mix, and then afteran incubation of 15 min at room temperature, 10 μL of reference agonistat historical EC₈₀ concentration and 20 μL of the GTPγ[³⁵S]:beads mix.The plates are covered with a top seal, mixed on an orbital shaker for 2min, and then incubated for 1 h at room temperature. Then the plates arecentrifuged for 10 min at 2000 rpm, incubated at RT 1 h and counted for1 min/well with a Perkin Elmer TopCount reader. Compounds are tested forantagonist activity at the human dopamine D_(2L) receptor (FAST-0101 G)at the following nanomolar concentrations, in duplicate: Antagonist(nM): 5, 15, 50, 150, 500, 1500, 5000, 15000.

Example B13 Increase of Neurite Outgrowth of Neurons that are Culturedwith Compounds of the Invention Neurite Outgrowth in Cortical Neurons

Compounds are tested to determine their ability to stimulate neuriteoutgrowth of cortical neurons. Standard methods are used to isolatecortical neurons. For the isolation of primary rat cortical neurons, thefetal brain from a pregnant rat at 17 days of gestation is prepared inLeibovitz's medium (L15; Gibco). The cortex is dissected out, and themeninges are removed. Trypsin (Gibco) is used to dissociate cortical Cwith DNAse I. The cells are triturated for 30 min with a pipette inDulbecco's Modified Eagle Media (“DMEM”; Gibco) with 10% Fetal BovineSerum (“FBS”) (Gibco) and centrifuged at 350×g for 10 min at RT. Thecells are suspended in Neurobasal medium supplemented with 2% B27(Gibco) and 0.5 mM L-glutamine (Gibco). The cells are maintained at30,000 cells per well of poly-L-lysine coated plates at 37° C. in 5%CO₂-95% air atmosphere. After adhesion, a vehicle control or compoundsof the invention are added at different concentrations to the medium.BDNF (50 ng/mL) is used as a positive control for neurite growth. Aftertreatment, cultures are washed in phosphate-buffered saline (“PBS”;Gibco) and fixed in glutaraldehyde 2.5% in PBS. Cells are fixed after 3days growth. Several pictures (˜80) of cells with neurites are taken percondition with a camera. The length measurements are made by analysis ofthe pictures using software from Image-Pro Plus (France). The resultsare expressed as mean (s.e.m.). Statistical analysis of the data isperformed using one way analysis of variance (ANOVA).

Neurite Outgrowth in Rat Mixed Cortical Cultures

Cortical mixed cultures are prepared from E18 Wistar rat embryos. Thecortices are dissected out and the tissue is cut to small pieces. Thecells are separated by 15-min incubation with DNase and papain. Thecells are collected by centrifugation (1500 rpm, 5 min). The tissue istriturated with a pipette and the cells are plated using the micro-isletprotocol (20,000 cells in 25 μL medium) on poly-L-lysine coated 48wells, in MEM supplemented with 2 mM glutamine, 0.1 μg/mL gentamicin,10% heat-inactivated fetal bovine serum (FBS-HI) and 10%heat-inactivated horse serum (HS-HI). After the cells attach to thewell, 250 μL medium is added to the wells. 4 h after plating, the mediumis changed to fresh medium (MEM with supplements and 5% HS-HI)containing test compound at 0.5, 5 and 50 nM concentrations. As positivecontrols BDNF (50, 100 and/or 150 ng/mL), and/or NGF (50 ng/mL and/or100 ng/mL) are used. After 2 days in vitro, the cell's conditioned mediaare collected from plates before fixing the cells. The media samples arecentrifuged 13,000 rpm 3 min to get rid of cell debris. The samples arestored at −20° C. for later analysis. Cells are formaldehyde-fixed andprocessed for immunocytochemistry. BDNF levels in the conditioned mediaare determined with a BDNF ELISA using the manufacturers (Promega, BDNFEmax® ImmunoAssay System, catalog number: G7610) instructions.

The cultures are fixed with 4% formaldehyde in 0.01 M PBS for 30 min andwashed once with PBS. The fixed cells are first permeabilized andnon-specific binding is blocked by a 30-min incubation with blockingbuffer containing 1% bovine serum albumin and 0.3% Triton X-100 in PBS.Rabbit anti-MAP-2 (dilution 1:1000, AB5622, Chemicon, in blockingbuffer) is used as a primary antibody. The cells are incubated with theprimary antibody for 48 h at +4° C., washed with PBS and incubated withsecondary antibody goat anti-rabbit IgG conjugated to Alexa Fluor568(1:200, A11036, Molecular Probes) for 2 h at RT. The immunopositivecells are visualized by a fluorescence microscope equipped withappropriate filter set, and documented by a high resolution imagecapturing. The number of cells per field (4 field per well) are counted,and the neurite outgrowth is quantified using Image Pro Plus software.The number of wells per compound concentration used is 6 (n=6). All dataare presented as mean±standard deviation (SD) or standard error of mean(SEM), and differences are considered to be statistically significant atthe p<0.05 level. Statistical analysis is performed using StatsDirectstatistical software. Differences between group means are analyzed byusing 1-way-ANOVA followed by Dunnet's test (comparison to the vehicletreated group).

Example B14 Use of an In Vivo Model to Evaluate the Ability of Compoundsto Enhance Cognition, Learning and Memory in Scopolamine Treated Rats

The two-trial object recognition paradigm developed by Ennaceur andDelacour in the rat is used as a model of episodic short term memory.Ennaceur, A., and Delacour, J. (1988), Behav. Brain Res. 31:47-59. Theparadigm is based on spontaneous exploratory activity of rodents anddoes not involve rule learning or reinforcement. The novel objectrecognition paradigm is sensitive to the effects of ageing andcholinergic dysfunction. See, e.g., Scali, C. et al, Neurosci. Letts.170:117-120, 1994; and Bartolini, L. et al, Biochem. Behay. 53:277-283,1996.

Male Sprague-Dawley rats between six and seven weeks old, weighingbetween 220-300 grams are obtained from Centre d'Elevage (Rue Janvier,B.P. 55, Le Genest-Saint-Isle 53940, France). The animals are housed ingroups of 2 to 4 in polypropylene cages (with a floor area of 1032 cm²)under standard conditions: at RT (22±2° C.), under a 12 h light/12 hdark cycle, with food and water provided ad libitum. Animals arepermitted to acclimate to environmental conditions for at least 5 daysbefore the experiment begins, and are numbered on their tails withindelible marker.

The experimental arena is a square wooden box (60 cm×60 cm×40 cm)painted dark blue, with 15 cm×15 cm black squares under a clearplexiglass floor. The arena and objects placed inside the arena arecleaned with water between each trial to eliminate any odor trails leftby rats. The arena is placed in a dark room illuminated only by halogenlamps directed towards the ceiling in order to produce a uniformly dimlight in the box of approximately 60 lux. The day before testing,animals are allowed to freely explore the experimental arena for 3 minin the presence of two objects (habituation). Animals to be tested areplaced in the experimental room at least 30 min before testing.

Novel object recognition test is comprised of two trials separated by aninterval of 120 min or 24 h. When agents that disrupt memory such as thecholinergic antagonist scopolamine are used an inter-trial interval of120 min is preferred. Alternatively a 24 h inter-trial interval is usedwhen studying effect of natural forgetting on novel object recognitiontask. During the first, or acquisition, trial (T₁), rats are placed inthe arena, where two identical objects have been previously placed. Thetime required for each animal to complete 15 sec. of object explorationis determined, with a cut-off time of 4 min. Exploration is consideredto be directing the nose at a distance less than 2 centimeters (“cm”)from the object and/or touching the object. During the second, ortesting, trial (T₂), one of the objects presented in the first trial isreplaced with an unknown or novel object, while the second, familiarobject is left in place. Rats are placed back in the arena for 3 min.,and exploration of both objects is determined. Locomotor activity ofrats (number of times rats cross grid lines visible under the clearplexiglass floor) is scored for during T₁ and T₂. At the conclusion ofthe experiments, the rats are sacrificed by an overdose of pentobarbitalgiven intraperitoneally.

The following parameters are measured as part of the novel objectrecognition task:

(1) time required to achieve 15 sec. of object exploration during T₁;(2) locomotor activity during T₁ (number of crossed lines); (3) timespent in active exploration of the familiar object during T₂(T_(Familiar)); (4) time spent in active exploration of the novel objectduring T₂ (T_(Novel)); and (5) locomotor activity during T₂ (number ofcrossed lines). The difference between time spent in active explorationof the novel object during T₂ and time spent in active exploration ofthe familiar object during T₂ (Δ T_(Novel)−T_(Familiar)) is evaluated.The % of animals in each group with T_(Nove)−T_(Familiar) greater thanor equal to 5 sec. is also derived; described as % of good learners.

Animals not meeting a minimal level of object exploration are excludedfrom the study as having naturally low levels of spontaneousexploration. Thus, only rats exploring the objects for at least fivesec. (T_(Nove1)+T_(Familiar)>5 sec.) are included in the study.

Animals are randomly assigned to groups of 14. Compounds of theinvention and controls are administered to animals the groups asfollows: Solutions of compounds are prepared freshly each day at aconcentration of 0.25 mg/mL using purified water or saline as vehicle.Donepezil, used as a positive control, and scopolamine are administeredsimultaneously in a single solution of saline (5 mL/kg) prepared freshlyeach day. Scopolamine is purchased from Sigma Chemical Co. (Catalog No.S-1875; St. Quentin Fallavier, France) is dissolved in saline to aconcentration of 0.06 mg/mL.

Donepezil is administered (e.g., intraperitoneally) 40 minutes beforethe acquisition trial (T1). Scopolamine is administered (e.g.,intraperitoneally) 30 minutes before the acquisition trial (T1). Vehicle(purified water) or test compound is administered (e.g., by gavage) 25minutes before the acquisition trial (T1), 5 min after scopolaminechallenge. The volume of administration is 5 mL/kg body weight forcompounds administered intraperitoneally, and 10 mL/kg for compoundsadministered orally.

Recognition scores and % of good learners for compounds of the inventionare determined.

Example B15 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia (Hyperactivity in PCP Treated Animals)

In vivo models of schizophrenia can be used to determine the ability ofthe compounds described herein to treat and/or prevent and/or delay theonset and/or the development of schizophrenia.

One exemplary model for testing the activity of one or more compoundsdescribed herein to treat and/or prevent and/or delay the onset and/ordevelopment of schizophrenia employs phencyclidine (PCP), which isadministered to the animal (e.g., non-primate (rat) or primate(monkey)), resulting in dysfunctions similar to those seen inschizophrenic humans. See Jentsch et al, Science 277:953-955, 1997; andPiercey et al, Life Sci. 43(4):375-385, 1988. Standard experimentalprotocols may be employed in this or in other animal models. Oneprotocol involves PCP-induced hyperactivity.

Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice/cage in OPTIMICE ventilated cages. All animals remain housed ingroups of 4 during the remainder of the study. All mice are acclimatedto the colony room for at least 2 weeks prior to testing and aresubsequently tested at an average age of 8 weeks of age. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12 h/12 h light/dark cycle. The RT is maintained between20 and 23° C. with a relative humidity maintained between 30% and 70%.Food and water are provided ad libitum for the duration of the study. Ineach test, animals are randomly assigned across treatment groups.

The following compounds are used for this study: 1) Compound of theinvention (0.03, 0.1, 0.3, 1, 3, 10 & 30 mg/kg) is dissolved in 5%PEG-200 in sterile water and administered p.o. 30 min prior to PCPinjection; 2) Clozapine (1.0 mg/kg) is dissolved in 10% DMSO andadministered i.p. 30 min prior to phencyclidine (PCP) injection; 3) PCP(5.0 mg/kg) is dissolved in sterile water and administered i.p.immediately before the 60 min test. All compounds are administered at adose volume of 10 mL/kg.

The open filed (OF) test assesses locomotor behavior, to measure mouselocomotor activity at baseline and in response to pharmacologicalagents. The open field chambers are Plexiglas square chambers(27.3×27.3×20.3 cm; Med Associates Inc., St Albans, Vt.) surrounded byinfrared photobeams (16×16×16) to measure horizontal and verticalactivity. The analysis is configured to divide the open field into acenter and periphery zone such that the infrared photobeams allowmeasurement of activity in the center and periphery of the field.Distance traveled is measured from horizontal beam breaks as the mousemoves whereas rearing activity is measured from vertical beam breaks.Mice (10 to 12 animals per treatment group) are brought to the activityexperimental room for at least 1 h acclimation to the experimental roomconditions prior to testing. Eight animals are tested in each run. Miceare administered vehicle (e.g., 10% DMSO or 5% PEG200 and 1% Tween 80),Compound of the invention, clozapine (positive control, 1 mg/kg ip) andplaced in the OF chambers for 30 min following which they are injectedwith either water or PCP and placed back in the OF chambers for a 60-minsession. At the end of each OF test session the OF chambers arethoroughly cleaned.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to PCP injection.PCP-induced activity is measured during the 60 min following PCPinjection. Statistical outliers that fall above or below 2 standarddeviations from the mean are removed from the final analyses. An effectis considered significant if p<0.05.

Example B16 Use of an In Vivo Model to Determine the Ability ofCompounds to Treat, Prevent and/or Delay the Onset and/or theDevelopment of Schizophrenia (Hyperactivity in Amphetamine TreatedAnimals)

Male mice (various strains e.g., C57B1/6J) from appropriate supplier(for example Jackson Laboratories, Bar Harbor, Me.) are used. Micetypically are received at 6-weeks of age. Mice are acclimated to thecolony room for at least two weeks prior to testing. During the periodof acclimation, mice are examined on a regular basis, handled, andweighed to assure adequate health and suitability and maintained on a 12h/12 h light/dark cycle. The RT is maintained between 20 and 23° C. witha relative humidity maintained between 30% and 70%. Food and water areprovided ad libitum for the duration of the study. In each test, animalsare randomly assigned between treatment groups.

The open field test (OF) is used to assess motor activity. The openfield chambers are plexiglas square chambers (e.g., 27.3×27.3×20.3 cm;Med Associates Inc., St Albans, Vt.) surrounded by infrared photobeamsources (16×16×16). The enclosure is configured to split the open fieldinto a center and periphery zone and the photocell beams are set tomeasure activity in the center and in the periphery of the OF chambers.Horizontal activity (distance traveled) and vertical activity (rearing)are measured from consecutive beam breaks.

On the day of testing, animals are brought to the experimental room forat least 1 h acclimation prior to start of treatment. Animals areadministered with vehicle, haloperidol (positive control, 0.1 mg/kg ip)or compound of the invention and placed in the OF. The time ofadministration of test compound to each animal is recorded. Baselineactivity is recorded for 30 min following which mice receive amphetamine(4 mg/kg) or water and are placed back in the OF chambers for a 60-minsession. At the end of each open field test session the OF chambers arethoroughly cleaned.

Typically ten to twelve mice are tested in each group. Test compounddoses typically range from 0.01 mg/kg to 60 mg/kg.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. Baseline activity ismeasured during the first 30 min of the test prior to amphetamineinjection. Amphetamine-induced activity is measured during the 60 minfollowing amphetamine injection. Statistical outliers that fall above orbelow 2 standard deviations from the mean are removed from the finalanalyses. An effect is considered significant if p<0.05. Total distancetraveled and total rearing following amphetamine administration arecompared between groups treated with compound and groups treated withvehicle and positive control haloperidol.

Example B17 Use of the In Vivo Conditioned Avoidance Response (CAR)Model to Determine the Ability of Compounds to Treat, Prevent and/orDelay the Onset and/or the Development of Schizophrenia

All currently approved antipsychotic agents (typical and atypical) areknown to have the ability to selectively suppress conditioned avoidanceresponse (CAR) behavior in the rat. This evidence makes CAR one of theprimary tests to assess antipsychotic activity of novel compounds.

The effects of compounds of the invention, at concentrations including0.1, 0.3, 1, 3, 10 and 20 mg/kg, p.o., in the conditioned avoidanceresponse model are assessed in the male Wistar rat. Risperidone (0.3mg/kg, s.c.) is used in the present study as a positive referencecompound.

For each testing session, animals are first placed for a 4-minhabituation period in a shuttlebox with an electrified grid floor. Then,rats are submitted to 30 trials spaced by intertrial intervals varyingat random between 20 and 30 sec. Each trial consists of a 10-sec. lightstimulus (conditioned stimulus, CS) followed by a 10-sec. electric footshock (unconditioned stimulus, US) in presence of the light presented inthe compartment where the rat is located. If the animal moves to theother compartment during the initial 10-sec. of the trial, the light isterminated (no shock is delivered) and the response is recorded as anavoidance response. If the rat changes compartment during the footshock, the light and the shock are terminated and the response isrecorded as an unconditioned response. If the rat does not changecompartment during the 10-sec. light period (CS) and during the 10-sec.shock+light period (US+CS), an escape failure is recorded. If a responseis made during an intertrial interval, the response is recorded as anintertrial crossing. Training is performed 5 days per week with onesession of 30 trials per day, until rats reach the performance criterionof 80% of avoidance response on at least two consecutive daily sessions.Once the performance criterion is reached, each animal is sequentiallyadministered with vehicle (15% HPBCD, p.o.), Compound of the invention(0.1, 0.3, 1, 3, 10 and 20 mg/kg, p.o.) and risperidone (0.3 mg/kg,s.c.). A minimal wash-out period of 48 h is allowed between 2treatments. During the wash-out period, animals are trained until theyrecover an avoidance performance of at least 80%.

Statistical analysis is performed using a Friedman two-way ANOVA byranks followed by the Wilcoxon matched-pairs signed-ranks test to testeach dose of the test compound administered versus vehicle controltreated rats.

Example B18 An Animal Model of the Negative Symptoms of Schizophrenia:Subchronic PCP-Induced Social Interaction Deficits

Phencyclidine (PCP) administered to humans as well to experimentalanimals induces full-spectrum of schizophrenia symptoms, includingnegative symptoms and cognitive deficits. A major symptom ofschizophrenia is considered to be social isolation/withdrawal as part ofthe cluster of negative symptoms. Subchronic treatment with PCP in ratsleads to the development of clear signs of social withdrawal as measuredby deficits in the interaction time with a cage intruder rat.

Male Sprague Dawley rats (˜150 g on arrival) from Harlan (Indiana) areused in this study. Upon receipt, rats are group housed in OPTI ratsventilated cages. Rats are housed in groups of 2-3/cage for theremainder of the study. During the period of acclimation, rats areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability. Rats are maintained on a 12 h/12 h light/darkcycle with the light on at 7:00 a.m. The RT is maintained between 20 and23° C. with a relative humidity maintained between 30% and 70%. Chow andwater are provided ad libitum for the duration of the study. Animals arerandomly assigned across treatment groups and balanced by age. Animalsare not disturbed between test days.

The following compounds are used. 1) Compound of the invention (0.3, 1and 3 mg/kg; p.o.) is dissolved in 3% Tween and PBS and administered 30min prior to test; 2) PCP (2 mg/kg; s.c.) is dissolved in saline andadministered twice daily for 5 days prior to test day; 3) Clozapine (2.5mg/kg; i.p.) is dissolved in 5% PEG:5% Tween 80 in saline andadministered 30 min prior to test. All compounds are administered at adose volume of 1 mL/kg.

For 5 days prior to test, rats are injected twice daily with either PCP(2 mg/kg; s.c) or saline (s.c). On day 6 and following a 30 minpretreatment with vehicle, clozapine or Compound of the invention, apair of rats, unfamiliar to each other, receiving the same treatment areplaced in a white plexiglas open field arena (24″×17″×8″) and allowed tointeract with each other for 6 min. Social interactions (‘SI’) include:sniffing the other rat; grooming the other rat; climbing over or underor around the other rat; following the other rat; or exploring theano-genital area of the other rat. Passive contact and aggressivecontact are not considered a measure of social interaction. The time therats spend interacting with each other during the 6 min test is recordedby a trained observer. The social interaction chambers are thoroughlycleaned between the different rats.

Data are analyzed by analysis of variance (ANOVA) followed by post-hocanalysis (e.g., Fischer, Dunnett) when appropriate. An effect isconsidered significant if p<0.05.

Example B19 An Animal Model of Extrapyramidal Syndrome (EPS):Measurement of Catalepsy in the Mouse Bar Test

Antipsychotic drugs are known to induce extrapyramidal syndrome (EPS) inanimals and in humans. An animal model considered to be predictive ofEPS is the mouse bar test, which measures cataleptic responses topharmacological agents.

Male C57B1I6J mice from Jackson Laboratories (Bar Harbor, Me.) are used.Mice are received at 6-weeks of age. Upon receipt, mice are assignedunique identification numbers (tail marked) and are group housed with 4mice/cage in OptiMICE ventilated cages. All animals remain housed ingroups of four during the remainder of the study. All mice areacclimated to the colony room for at least two weeks prior to testingand are subsequently tested at an average age of 8 weeks. During theperiod of acclimation, mice are examined on a regular basis, handled,and weighed to assure adequate health and suitability. Animals aremaintained on a 12 h/12 h light/dark cycle. The RT is maintained between20 and 23° C. with a relative humidity maintained between 30% and 70%.Chow and water are provided ad libitum for the duration of the study. Ineach test, animals are randomly assigned across treatment groups.

The following compounds are used for this study. 1) Compound of theinvention (0.03, 0.1, 0.3, 1, 3, 10, 30 mg/kg) is dissolved in 3% Tweenin PBS and administered orally at a dose volume of 10 mL/kg; 2)Haloperidol (2 mg/kg) is dissolved in 10% DMSO and administered i.p. ata dose volume of 10 mL/kg.

The front paws of a mouse are placed on a horizontal metal bar raised 2″above a Plexiglas platform and time is recorded for up to 30 sec. pertrial. The test ends when the animal's front paws return to the platformor after 30 sec. The test is repeated three times and the average of thethree trials is reported as the intensity index of catalepsy.Antipsychotic agents such as haloperidol cause rigidity as a sideeffect. Animals treated with haloperidol will hold on to the bar withoutmoving for several minutes. Mice are brought to the activityexperimental room for at least 1 h acclimation to the experimental roomconditions prior to testing. Following injection of either vehicle,Compound of the invention, or haloperidol, catalepsy is assessed at 3time points: 30 min, 1 h and 3 h. At the end of each trial, theapparatus is thoroughly cleaned with 70% ethanol.

Data are analyzed by analysis of variance (ANOVA) followed by post-hoccomparisons with Fisher Tests when appropriate. An effect is consideredsignificant if p<0.05.

Example B20 Use of the 5-Choice Serial Reaction Task to Determine theAbility of Compounds to Enhance Attention/Vigilance and ReduceImpulsivity

Attention and impulsivity are characteristic of several disease states.The continuous performance test (CPT), used in humans, is capable ofdetecting attention deficits in a number of disorders, includingattention deficit hyperactivity disorder, schizophrenia and mildcognitive impairment. The pre-clinical analogue of the CPT is the5-choice serial reaction time task (5CSRTT). In this operant-based test,rats are required to be attentive and withhold responding while theymonitor 5 apertures for the appearance of a brief stimulus light in oneof the apertures. The brief illumination of the stimulus light in the5CSRTT is analogous to the appearance of the “correct” letters in theCPT in humans. Upon observing the stimulus light, the rat must nose-pokein the corresponding aperture to receive a food reward. The 5CSRTTallows the measurement of similar behavioral responses as the CPT,including accuracy, speed of responding, impulsive and compulsiveresponding. In this study, drug tests are performed under altered testparameters which result in increased premature responding. Thispremature responding is hypothesized to indicate impulsivity, e.g., afailure to withhold an inappropriate response, and has been shown to besensitive to atomoxetine.

Thirteen male Long-Evans rats (275-300 g) are obtained from HarlanLaboratories, Indianapolis, Ind. At the time of testing for the currentstudy, the rats are approximately 16-18 months old. Upon arrival, therats are assigned unique identification numbers (tail marked). Rats aresingle-housed in OptiRAT cages and acclimated for 7 days prior tocommencing a food-restriction regimen: rats are held at 85% ofage-matched free-feeding control bodyweights, receiving approximately10-20 g of rat chow daily. Water is provided ad libitum, except duringtesting. Animals are maintained in a 12 h/12 h light/dark cycle (lightson at 0700 EST) with RT maintained at 22±2° C. and the relative humiditymaintained at approximately 50%. All animals are examined, handled andweighed prior to initiation of the study to assure adequate health andsuitability and to minimize non-specific stress associated with testing.The 5CSRTT sessions are performed during the animal's light cycle phase.All experiments and procedures are approved by the Institutional AnimalCare and Use Committee of PsychoGenics, Inc.

The apparatus consists of 10 aluminum and Plexiglas chambers with gridfloors (width 31.5 cm, depth 25.0 cm, height 33.0 cm), housed insound-attenuating cabinets. Each cabinet is fitted with a low-levelnoise extractor fan which also helped to mask external noise. The leftwall of each chamber is concavely curved with 5 apertures evenly spaced,located approximately 2.5 cm from the floor. Each aperture contains astandard 3W LED to serve as stimulus lights. The opposite wall containsa food magazine, located approximately 3.0 cm from the floor. Eachchamber is illuminated with a 3W house-light located in the center ofthe ceiling panel. After each test session the apparatus is cleaned with70% ethanol.

The following compounds are used for this study. 1) Compound of theinvention is dissolved in saline, and administered p.o. at 0.1, 0.3 and1.0 mg/kg, 30 min prior to testing at 1 mL/kg body weight; 2) Thereference compound atomoxetine (1.0 mg/kg) is dissolved in saline andadministered i.p. 30 min prior to testing at 1 mL/kg body weight.

Training: Animals are trained to monitor the five apertures for stimuluslight illumination. Each session is initiated by the illumination of thehouse light, and the delivery of a food reward into the magazine. Thefirst trial begins when the rat opens the magazine to obtain the foodpellet. After the inter-trial interval (ITI) one of the stimulus lightsis illuminated for 500 msec. The rat must nose-poke in the illuminatedaperture either during or within 5 sec. of stimulus light illumination.Such a response is defined as a correct response, and is rewarded withdelivery of a food pellet. Collection of the pellet initiates the nexttrial. A nose-poke response in a non-illuminated aperture (incorrectresponse) or a nose-poke after the 5 sec. limited hold (missed trial)results in termination of the trial with extinction of the house-lightand imposition of a time-out period.

Testing: After acquisition of the 5CSRTT with a high level of accuracy(at least 75% correct, at least 50 trials completed per session), drugtesting begins. Animals are treated with test compound (various doses,appropriate vehicle), vehicle and positive control (atomoxetine 1 mg/kgip). During drug test sessions, the ITI is varied between 10, 7, 5 or 4sec. in duration, presented in groups of 4 trials (each of whichcontains 1 trial at each ITI duration in a randomized order). Thesession ends when 60 min have elapsed. All rats receive all drugtreatments, according to a randomized-order within-subjects design. Drugtests are performed on Wednesdays and Fridays of each week, only whenrats perform at least 75% correct trials for a minimum of 50 trials inthe previous test session.

Measures obtained during the test sessions are: (1) percent correct,defined as the number of correct trials×100, divided by the total numberof correct and incorrect trials, (2) missed trials, defined asresponding beyond the 5 sec. limited hold or failing to respond, (3)correct latency, defined as the time taken to make a correct responseafter the illumination of the stimulus, (4) magazine latency, defined asthe time taken to enter the magazine to collect the food pellet aftermaking a correct response, (5) premature responding, defined as thetotal number of nose-poke responses made during the IT', and (6)perseverative responding, defined as the total number of additionalresponses emitted after the initial nose-poke.

Example B21 An Animal Model to Test the Anxiolytic Effects of CompoundsUsing the Elevated Plus Maze (EPM) Test

This study aims to test the anxiolytic properties of compounds of theinvention using the elevated plus maze (EPM) test in C57B1/6J mice.

Male C57B1/6J mice from Jackson Laboratories (Bar Harbor, Me.) are usedfor the open field study. Mice are received at 6-weeks of age. Uponreceipt, mice are assigned unique identification numbers (tail marked)and are group housed with 4 mice/cage in OPTI mouse ventilated cages.All animals remain housed in groups of four during the remainder of thestudy. All mice are acclimated to the colony room for approximately 2week prior to testing and are subsequently tested at an average age of 8weeks of age. During the period of acclimation, mice and rats areexamined on a regular basis, handled, and weighed to assure adequatehealth and suitability. Animals are maintained on a 12 h/12 h light/darkcycle. The RT is maintained between 20 and 23° C. with a relativehumidity maintained between 30% and 70%. Chow and water are provided adlibitum for the duration of the study. In each test, animals arerandomly assigned across treatment groups. All animals are euthanizedafter the completion of the study.

The following compounds are used for this study: 1) Compound of theinvention (0.03, 0.1 and 1 mg/kg) is dissolved in 5% PEG200/H₂O andadministered orally at a dose volume of 10 mL/kg 30 min prior to test;2) Diazepam (2.5 mg/kg) is dissolved in 45% hydroxypropyl-β-cyclodextrinand administered orally at a dose volume of 10 mL/kg 30 min prior totest.

The elevated plus maze test assesses anxiety. The maze (Hamilton Kinder)consists of two closed arms (14.5 h×5 w×35 l cm) and two open arms (6w×35 l cm) forming a cross, with a square center platform (6×6 cm). Allvisible surfaces are made of black acrylic. Each arm of the maze isplaced on a support column 56 cm above the floor. Antistatic black vinylcurtains (7′ tall) surround the EPM to make a 5′×5″ enclosure. Animalsare brought to acclimate to the experimental room at least 1 h beforethe test. Mice are placed in the center of the elevated plus maze facingthe closed arm for a 5-min run. All animals are tested once. The timespent, distance traveled and entries in each arm are automaticallyrecorded by the computer. The EPM is thoroughly cleaned after eachmouse.

Data are analyzed using analysis of variance (ANOVA) followed byFisher's LSD post hoc analysis when appropriate. An effect is consideredsignificant if p<0.05.

Example B22 Cell Culture and Cell Viability Assay

SH-SY5Y cells cultured in DMEM/F12 media supplemented with 10% FBS wereseeded in 96-well microplates at 150,000 cells/cm². After 24 h, cellswere depleted from FBS and kept in culture for 24 h before theexperiment. A stock solution was prepared by dissolving the calciumionophore 4-Br-A23187 (Calbiochem Cat. No 100107) in DMSO at 25 mM.Cells were then treated with 4-Br-A23187 (2 μM), hydrogen peroxide (300μM) or the mitochondrial toxin rotenone (25 μM) in the presence ofvehicle or Compound of the Invention for 24 h. Cell death was determinedby measurements of LDH release according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany). Cell viability was determined bymeasuring the capacity of cells to metabolize MTS tetrazolium (MTS)according to the Cytotoxicity Detection KitPlus (Roche, Mannheim,Germany) and MTS reduction is assessed by the CellTiter 96® AQueous OneSolution Cell Proliferation assay (Promega Corporation, Madison, Wis.,USA). Compounds were screened at 10 nM, using DMSO as vehicle. Assayresults for the experiments with Br-A23187 are presented as the MTSreduction capacity (cell viability) of untreated cells (control),4-Br-A23187-treated cells (vehicle), and co-incubation of Br-A23187 withCompounds of the Invention treated cells and usingp-trifluoromethoxyphenylhydrazone (FCCP) at 10 μM for 30 min as acontrol. This assay assesses the ability of the test compounds toprotect against cell death that is mediated by mitochondrialdysfunction. In the assay, the calcium ionophore 4-Br-A23187 is used tochallenge the cells, causing calcium levels to rise in mitochondria,which leads to depolarization and cell death. Test compounds areassessed for their ability to prevent cell death in response tochallenge with 4-Br-A23187.

TABLE 5 Relative Cytoprotection efficiency of compounds of the inventionCompound No. Mean Standard Error p value Vehicle 0 0 ns Control 1001.47E−06 ns 1 −1.10264 48.94656 ns 2 −4.4068 30.13848 ns 3 35.0826311.90545 ns 5 28.81883 6.21819 0.0435 6 27.59688 3.322046 0.0142 915.84906 12.76087 ns 11 37.63225 18.00517 ns 12 35.74884 18.90774 ns 1319.74211 12.6988 ns 17 10.7958 19.56162 ns 18 26.00401 19.9292 ns

Example B23 Cell Culture and Cell Viability Assay Cell Culture

SH-SY5Y cells stably transfected with a doxycyline-inducible wild-typeα-synuclein (α-syn) gene along with control SH-SY5Y cellsover-expressing the β-galactosidase (β-gal) gene (a gift from L.Stefanis, Division of Basic Neurosciences, Biomedical ResearchFoundation of the Academy of Athens, Athens, Greece) are cultured asdescribed by Vekrellis et al. (Vekrellis K, Xilouri M, Emmanouilidou E,Stefanis L. (2009). Inducible over-expression of α-syn in human neuronalcells leads to caspase-dependent non-apoptotic death. J Neurochem 109,1348-1362). In accordance with this method, cells are cultured andmaintained in RPMI 1640, 10% fetal bovine serum supplemented with 250μg/mL G418 and 50 μg/mL Hygromycin B. Expression of α-syn is switchedoff in stock cultures with doxycycline (2 μg/mL). For experimentalprocedures, cells are plated at (4−8×10⁴ cells/cm²) and differentiatedin absence of doxycycline and in the presence of 20 μM all-transretinoic acid (RA) (Sigma, St Louis, Mo., USA).

Viability Assay

Cells are cultured in 96-well plates. After 24 h, cells are treated withRA and Compounds of Invention at 0.1 and 10 nM in the absence ofdoxycyline. Culture medium with RA and drugs is fully replaced after 7days. Cell viability is measured by the release of lactate dehydrogenase(LDH) from necrotic cells into the culture medium and by measuring thecapacity of cells to metabolize MTS tetrazolium (MTS) after 14 days inculture. LDH leakage is assessed according to the Cytotoxicity DetectionKitPlus (Roche, Mannheim, Germany) and MTS reduction is assessed by theCellTiter 96® AQueous One Solution Cell Proliferation assay (PromegaCorporation, Madison, Wis., USA).

Immunoblotting of α-Synuclein and α-Synuclein Aggregates

Cells stably expressing α-synuclein are cultured in 6-well plates at adensity of 4×10⁴ cells/cm² cells per well. Cells are differentiated andtreated with Compound of the Invention at 10 nM in absence of dox after24 h of plating. Drug treatments are repeated after 7 days in freshlyprepared medium containing RA. After 14 days, cells are washed twicewith cold PBS and lysed in lysys buffer containing 1% Triton X-100, 20mM HEPES, 150 mM NaCl, 10% glycerol, 1 mM EGTA, 1.5 mM MgCl₂, 1 mM PMSFpH 7.4, and 1× protease inhibitor mixture (Roche, Mannheim, Germany).Lysates are homogenized and subjected to four successive freeze-thawcycles to disrupt membranes. Triton soluble fractions and tritoninsoluble pellets are obtained by ultracentrifugation at 100,000×g for30 min at 4° C. The concentration of protein in each fraction isdetermined by BCA assay (Thermo Scientific). Samples from total, solubleand triton insoluble fractions, are boiled in 1× sample buffer (20 mMTris, 1% glycerol, 180 mM β-mercaptoethanol, 0.003% bromophenol blue,and 2% SDS, pH 6.8), loaded on 12% SDS-PAGE gels, and transferred topolyvinylidene difluoride (PVDF) membranes (0.2 μM-pore immobilonBiorad). Membranes are blocked in 1×TBS-Tween (20 mM Tris, pH 7.4, 150mM NaCl, and 0.2% Tween 20) containing 5% milk for 1 h and incubatedovernight at 4° C. with the following primary antibodies in blockingsolution at the indicated dilutions: monoclonal anti-α-synuclein α-syn-1(1:1000; BD Transduction Laboratories). (Perrin, R. J., Payton, J. E.,Barnett, D. H., Wraight, C. L., Woods, W. S., Ye, L., and George, J. M.(2003). Epitope mapping and specificity of the anti-α-synucleinmonoclonal antibody Syn-1 in mouse brain and cultured cell lines.Neurosci Lett 349, 133-135), and monoclonal vimentin (1:1000; BDPharMingen). Primary antibodies are detected with secondary anti-mouseantibodies conjugated to HRP (1:5000).

Isolation of RNA and RT-Quantitative PCR(RT-qPCR)

SH-SY5Y cells stably over-expressing α-syn are treated with Compound ofthe Invention (10 nM). Total RNA from these cells as well as controlcells not treated with Compound is extracted using the E.Z.N.A RNAextraction Kit (OMEGAbiotek, Norcross, Ga.). 1 μg of RNA is reversetranscribed to cDNA using the M-Mulv reverse transcriptase enzyme(Promega Corporation, Madison, Wis., USA). RT-qPCR of cDNA templates iscarried out using TAQMAN probes for human α-synuclein (Hs00240906_M1)and TAQMAN masterMix (Applied Biosystems) and a Mx3005P real-time PCRsystem (Agilent Technologies Inc., Santa Clara, Calif.). Levels ofalpha-tubulin mRNA are used to normalize the amounts of total RNAbetween samples. Fold changes are calculated as described by (Pfaffl, M.W. (2001). A new mathematical model for relative quantification inreal-time RT-PCR. Nucleic Acids Res 29, e45).

All references throughout, such as publications, patents, patentapplications and published patent applications, are incorporated hereinby reference in their entireties.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is apparent to those skilled in the art that certainminor changes and modifications will be practiced. Therefore, thedescription and examples should not be construed as limiting the scopeof the invention.

1. A compound of the formula (IA):

or a salt or solvate thereof; wherein: R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(4a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; eachR^(2a) and R^(2b) is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety; each R^(4a) and R^(4b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) and R^(4b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(4a) and R¹ are taken together toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,or R^(4a) and R^(2a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl; each X¹,X² and X³ is independently N, CH or CR⁶; each m, n, o or p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8C), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) isindependently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other thanhydroxyl; and Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; provided that at leastone of X¹, X² and X³ is CH or CR⁶ and provisions (1)-(4) apply: (1) wheneach m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, acyloxy, cyano,alkynyl, acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), oramino substituted with one or two substituted or unsubstituted C₁-C₈alkyl; (2) when each m, n, o and p is 0 and R⁵ is methyl, then Q issubstituted or unsubstituted aryl other than unsubstituted phenyl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl,substituted or unsubstituted heterocyclyl, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, alkynyl, aminocarbonylalkoxy, a group of the formula—CR⁹═CR^(10a)R^(10b), or amino substituted with one or two substitutedor unsubstituted C₁-C₈ alkyl; (3) wherein at least one of m, n, o and pis 1 and R⁵ is H, then Q substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substitutedor unsubstituted heterocyclyl, substituted or unsubstituted amino,aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b); and (4) wherein at least one of m, n, o and p is 1and R⁵ is methyl, then Q substituted or unsubstituted aryl, substitutedor unsubstituted heteroaryl, substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, substitutedor unsubstituted heterocyclyl other than a substituted piperazinyl,aminoacyl, acyloxy, carboxyl, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR^(10a)R^(10b), or aminosubstituted with one or two substituted or unsubstituted C₁-C₈ alkyl. 2.The compound of claim 1, wherein the compound is of the formula (C1),(C2), (C3), (C4) or (C5):

wherein: R¹ is H or substituted or unsubstituted C₁-C₈ alkyl; R⁵ is H orunsubstituted C₁-C₈ alkyl; R⁶ is H, halo, or substituted orunsubstituted C₁-C₈ alkyl; R^(8C) is H, OH or substituted orunsubstituted C₁-C₈ alkyl; R^(8d) is H or substituted or unsubstitutedC₁-C₈ alkyl, and the

bond indicates the presence of either an E or Z double bondconfiguration; Y is O or NR¹¹; each R¹¹, R^(12a) and R^(12b) isindependently H or substituted or unsubstituted C₁-C₈ alkyl; each X¹ andX³ is independently CH or N; and D is substituted or unsubstituted arylor substituted or unsubstituted heteroaryl; provided that when thecompound is of the formula (C5), D is other than unsubstituted phenyl.3. The compound of claim 2, wherein the compound is of the formula (C1).4. The compound of claim 2, wherein the compound is of the formula (C2).5. The compound of claim 2, wherein the compound is of the formula (C3).6. The compound of claim 2, wherein the compound is of the formula (C4).7. The compound of claim 2, wherein the compound is of the formula (CS).8. The compound of claim 1, wherein R¹ is H or methyl.
 9. The compoundof claim 1, wherein R⁵ is H or methyl.
 10. The compound of claim 1,wherein X¹ is CH.
 11. The compound of claim 1, wherein X³ is CH.
 12. Thecompound of claim 1, wherein R⁶ is H, chloro or methyl.
 13. The compoundof claim 12, wherein R⁶ is methyl.
 14. The compound of claim 3, whereinR^(8c) is H, OH or methyl.
 15. The compound of claim 14, wherein R^(8d)is H, or unsubstituted C₁-C₈ alkyl.
 16. The compound of claim 4, whereinR^(8d) is H or methyl.
 17. The compound of claim 6, wherein Y is NR¹¹.18. The compound of claim 17, wherein R¹¹ is H or methyl.
 19. Thecompound of claim 17, wherein each R^(12a) and R^(12b) is H.
 20. Thecompound of claim 17, wherein D is selected from the group consisting ofphenyl, 4-fluorophenyl, pyridin-4-yl, pyridine-3-yl,6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and4-phenylthiazol-2-yl.
 21. The compound of claim 2, wherein D is selectedfrom the group consisting of 4-fluorophenyl, pyridin-4-yl,pyridine-3-yl, 6-methylpyridin-3-yl, thiophen-2-yl, thiazol-2-yl, and4-phenylthiazol-2-yl.
 22. The compound of claim 1, wherein Q issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.
 23. A compound of the formula (IB):

or a salt or solvate thereof; wherein: R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, thiol, thioalkyl, substituted or unsubstituted amino,acylamino, aminoacyl, aminocarbonylamino, aminocarbonyloxy,aminosulfonyl, sulfonylamino, sulfonyl or carbonylalkylenealkoxy, or R¹and R^(2a) are taken together to form a propylene (—CH₂CH₂CH₂—) moietyor a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety, or R¹ and R^(4a) are taken together to form anethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety; eachR^(2a) and R^(2b) is independently H, substituted or unsubstituted C₁-C₈alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(2a) and R^(2b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(2a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(2a)and R^(3a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(2a) and R^(4a) are taken togetherto form a methylene (—CH₂—) moiety or an ethylene (—CH₂CH₂—) moiety;each R^(3a) and R^(3b) is independently H, substituted or unsubstitutedC₁-C₈ alkyl, halo, cyano, hydroxyl, alkoxy, nitro, substituted orunsubstituted amino, acyloxy, acylamino, aryl, heteroaryl, cycloalkyl,heterocyclyl, or R^(3a) and R^(3b) are taken together with the carbon towhich they are attached to form a carbonyl moiety or a cycloalkylmoiety, or R^(3a) and R¹ are taken together to form a propylene(—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—) moiety, or R^(3a)and R^(2a) are taken together to form an ethylene (—CH₂CH₂—) moiety or apropylene (—CH₂CH₂CH₂—) moiety, or R^(3a) and R^(4a) are taken togetherto form a propylene (—CH₂CH₂CH₂—) moiety or a butylene (—CH₂CH₂CH₂CH₂—)moiety; each R^(4a) and R^(4b) is independently H, substituted orunsubstituted C₁-C₈ alkyl, halo, cyano, nitro, substituted orunsubstituted amino, hydroxyl, alkoxy, acyloxy, acylamino, aryl,heteroaryl, cycloalkyl, heterocyclyl, or R^(4a) and R^(4b) are takentogether with the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or R^(4a) and R¹ are taken together toform an ethylene (—CH₂CH₂—) moiety or a propylene (—CH₂CH₂CH₂—) moiety,or R^(4a) and R^(2a) are taken together to form a methylene (—CH₂—)moiety or an ethylene (—CH₂CH₂—) moiety, or R^(4a) and R^(3a) are takentogether to form a propylene (—CH₂CH₂CH₂—) moiety or a butylene(—CH₂CH₂CH₂CH₂—) moiety; R⁵ is H or unsubstituted C₁-C₈ alkyl; each X¹,X² and X³ is independently N, CH or CR⁶; each m, n, o or p isindependently 0 or 1; each R⁶ is independently hydroxyl, nitro, cyano,halo, C₁-C₈ perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl,substituted or unsubstituted C₂-C₈ alkenyl, substituted or unsubstitutedC₂-C₈ alkynyl, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ perhaloalkoxy, substituted orunsubstituted C₁-C₈ alkoxy, substituted or unsubstituted aryloxy,carboxyl, carbonylalkoxy, thiol, substituted or unsubstitutedheterocyclyl, substituted or unsubstituted aralkyl, thioalkyl,substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8C), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) isindependently H, hydroxyl, alkoxy, halo, substituted or unsubstitutedC₁-C₈ alkyl, substituted or unsubstituted C₃-C₈ cycloalkyl, substitutedor unsubstituted C₂-C₈ alkenyl, C₁-C₈ perhaloalkyl, carboxyl,carbonylalkoxy, substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, C₁-C₈ alkyl substituted with a carbonylalkoxy,carboxyl or acylamino moiety, or is taken together with a geminalR^(8(a-h)) to form a substituted or unsubstituted methylene moiety or amoiety of the formula —OCH₂CH₂O—, or is taken together with a geminalR^(8(a-h)) and the carbon to which they are attached to form a carbonylmoiety or a cycloalkyl moiety, or is taken together with a vicinalR^(8(a-h)) and the carbon atoms to which they are attached to form asubstituted or unsubstituted C₃-C₈ cycloalkyl, substituted orunsubstituted C₃-C₈ cycloalkenyl, or substituted or unsubstitutedheterocyclyl moiety, or is taken together with a vicinal R^(8(a-h)) toform a bond provided when an R^(8(a-h)) is taken together with a vicinalR^(8(a-h)) to form a bond, the geminal R^(8(a-h)) is other thanhydroxyl; and Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino, alkoxy,aminoacyl, acyloxy, carboxyl, carbonylalkoxy, cyano, alkynyl,aminocarbonylalkoxy, acylamino, or is a group of the formula—CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or a substituted or unsubstitutedC₁-C₈ alkyl and R^(10a) and R^(10b) are taken together with the carbonto which they are attached to form a substituted or unsubstitutedcycloalkyl, cycloalkenyl or heterocyclyl moiety; provided that at leastone of X¹, X² and X³ is CH or CR⁶ and provisions (1)-(3) apply: (1) wheneach m, n, o and p is 0 and R⁵ is H, then Q is substituted orunsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, cyano, alkynyl, aminocarbonylalkoxy,acylamino, a group of the formula —CR⁹═CR^(10a)R^(10b), or aminosubstituted with one or two substituted or unsubstituted C₁-C₈ alkyl;(2) when each m, n, o and p is 0 and R⁵ is unsubstituted C₁-C₈ alkyl,then Q is substituted or unsubstituted aryl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted or unsubstituted amino,aminoacyl, acyloxy, carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy,acylamino, or is a group of the formula —CR⁹═CR¹⁰aR^(10b); and (3) whenat least one of m, n, o and p is 1 and R⁵ is H, then Q is substituted orunsubstituted aryl other than unsubstituted phenyl, substituted orunsubstituted heteroaryl, substituted or unsubstituted C₃-C₈ cycloalkyl,substituted or unsubstituted C₃-C₈ cycloalkenyl, substituted orunsubstituted heterocyclyl, substituted amino, aminoacyl, acyloxy,cyano, alkynyl, aminocarbonylalkoxy, or is a group of the formula—CR⁹═CR^(10a)R^(10b).
 24. The compound of claim 23, wherein Q issubstituted or unsubstituted aryl or substituted or unsubstitutedheteroaryl.
 25. A compound of the formula (J-1), (J-2), (J-3), (J-4), or(J-5):

or a salt or solvate thereof, wherein: R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(8a), R^(8b), R^(8c), R^(8d),R^(8e), R^(8f), R^(8g) and R^(8h) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³,R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X² and X³ is independently N, CH orCR⁶; each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8C), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h), wherepresent, is independently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl,—S-aryl, —S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety.
 26. A compound of the formula (K-1), (K-2), (K-3), (K-4), or(K-5):

or a salt or solvate thereof, wherein: R¹ is H, hydroxyl, substituted orunsubstituted C₁-C₈ alkyl, substituted or unsubstituted C₂-C₈ alkenyl,substituted or unsubstituted C₂-C₈ alkynyl, perhaloalkyl, acyl, acyloxy,carbonylalkoxy, substituted or unsubstituted heterocyclyl, substitutedor unsubstituted aryl, substituted or unsubstituted heteroaryl,substituted or unsubstituted aralkyl, C₁-C₈ perhaloalkoxy, alkoxy,aryloxy, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl or carbonylalkylenealkoxy; each R^(2a), R^(2b) R^(3a), R^(3b),R^(4a), R^(4b), R^(10a) and R^(10b) is independently H, hydroxyl, nitro,cyano, halo, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,perhaloalkyl, acyl, acyloxy, carbonylalkoxy, substituted orunsubstituted heterocyclyl, substituted or unsubstituted aryl,substituted or unsubstituted heteroaryl, substituted or unsubstitutedaralkyl, C₁-C₈ perhaloalkoxy, alkoxy, aryloxy, carboxyl, thiol,thioalkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, alkylsulfonylamino, or carbonylalkylenealkoxy, or is takentogether with the carbon to which it is attached and a geminal R², R³,R⁴ or R¹⁰ to form a carbonyl moiety or a cycloalkyl moiety; R⁵ is H orunsubstituted C₁-C₈ alkyl; each X¹, X² and X³ is independently N, CH orCR⁶; each R⁶ is independently hydroxyl, nitro, cyano, halo, C₁-C₈perhaloalkyl, substituted or unsubstituted C₁-C₈ alkyl, substituted orunsubstituted C₂-C₈ alkenyl, substituted or unsubstituted C₂-C₈ alkynyl,substituted or unsubstituted aryl, substituted or unsubstitutedheteroaryl, C₁-C₈ perhaloalkoxy, substituted or unsubstituted C₁-C₈alkoxy, substituted or unsubstituted aryloxy, carboxyl, carbonylalkoxy,thiol, substituted or unsubstituted heterocyclyl, substituted orunsubstituted aralkyl, thioalkyl, —S(O)-alkyl, —S(O)-aryl,—S(O)-aralkyl, substituted or unsubstituted amino, acylamino, aminoacyl,aminocarbonylamino, aminocarbonyloxy, aminosulfonyl, sulfonylamino,sulfonyl, carbonylalkylenealkoxy, alkylsulfonylamino or acyl; eachR^(8a), R^(8b), R^(8C), R^(8d), R^(8e), R^(8f), R^(8g) and R^(8h) isindependently H, hydroxyl, alkoxy, acyloxy, thiol, —S-alkyl, —S-aryl,—S-aralkyl, —S(O)-alkyl, —S(O)-aryl, —S(O)-aralkyl, —SO₂-alkyl,—SO₂-aryl, —SO₂-aralkyl, substituted or unsubstituted amino, halo,substituted or unsubstituted C₁-C₈ alkyl, substituted or unsubstitutedC₃-C₈ cycloalkyl, substituted or unsubstituted C₂-C₈ alkenyl, C₁-C₈perhaloalkyl, carboxyl, carbonylalkoxy, substituted or unsubstitutedaryl, substituted or unsubstituted heteroaryl, C₁-C₈ alkyl substitutedwith a carbonylalkoxy, carboxyl or acylamino moiety, or is takentogether with a geminal R^(8(a-h)) to form a substituted orunsubstituted methylene moiety or a moiety of the formula —OCH₂CH₂O—, oris taken together with a geminal R^(8(a-h)) and the carbon to which theyare attached to form a carbonyl moiety or a cycloalkyl moiety, or istaken together with a vicinal R^(8(a-h)) and the carbon atoms to whichthey are attached to form a substituted or unsubstituted C₃-C₈cycloalkyl, substituted or unsubstituted C₃-C₈ cycloalkenyl, orsubstituted or unsubstituted heterocyclyl moiety, or is taken togetherwith a vicinal R^(8(a-h)) to form a bond provided when an R^(8(a-h)) istaken together with a vicinal R^(8(a-h)) to form a bond, the geminalR^(8(a-h)) is other than hydroxyl and thiol; and Q is substituted orunsubstituted aryl, substituted or unsubstituted heteroaryl, substitutedor unsubstituted C₃-C₈ cycloalkyl, substituted or unsubstituted C₃-C₈cycloalkenyl, substituted or unsubstituted heterocyclyl, substituted orunsubstituted amino, alkoxy, aminoacyl, acyloxy, carboxyl,carbonylalkoxy, cyano, alkynyl, aminocarbonylalkoxy, acylamino, or is agroup of the formula —CR⁹═CR^(10a)R^(10b), wherein R⁹ is H or asubstituted or unsubstituted C₁-C₈ alkyl and R^(10a) and R^(10b) aretaken together with the carbon to which they are attached to form asubstituted or unsubstituted cycloalkyl, cycloalkenyl or heterocyclylmoiety.
 27. A compound selected from the group consisting of compounds1-161, or a pharmaceutically acceptable salt thereof.
 28. Apharmaceutical composition comprising (a) a compound of claim 1 or apharmaceutically acceptable salt thereof and (b) and a pharmaceuticallyacceptable carrier.
 29. A method of treating a cognitive disorder,psychotic disorder, neurotransmitter-mediated disorder or a neuronaldisorder in an individual comprising administering to an individual inneed thereof an effective amount of a compound of claim
 1. 30. A methodof treating a cognitive disorder, psychotic disorder,neurotransmitter-mediated disorder or a neuronal disorder in anindividual comprising administering to an individual in need thereof aneffective amount of a compound selected from the group consisting ofcompounds 1-161.
 31. (canceled)
 32. A kit comprising a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof andinstructions for use in the treatment of a cognitive disorder, psychoticdisorder, neurotransmitter-mediated disorder or a neuronal disorder.